Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention Thomas Brioche, Allan Pagano, Guillaume Py, Angèle Chopard

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Thomas Brioche, Allan Pagano, Guillaume Py, Angèle Chopard. Muscle wasting and aging: Experi- mental models, fatty infiltrations, and prevention. Molecular Aspects of Medicine, Elsevier, 2016,32 p. ￿10.1016/j.mam.2016.04.006￿. ￿hal-01837630￿

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Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of and therapies, hormone replacement exercise, which by mechanisms cellular and and molecular modulation and efficiency the on data main the reviewwe part, last the In age. fate advancing FAP both in implicated players fibro/adipogenic cellular some called linking by cells progenitors stem mesenchymal muscle-resident and aging concerning of experiments human or animal, cell, involving models experimental available on focus mainly first We points. main three address to aims review present The inactivity. to linked closely is factor important new this that emphasized or infiltrations fatty of importance i the recognized increasingly have Studies muscle wasting. of analysis comprehensive devise to opportunities the together bringing models, experimental several of means by deciphered been have involved. processes Muscle-deconditioning mechanisms molecular and cellular the of understanding is requires It aging challenge. and wasting muscle during performance physical strength, muscle mass, muscle maintain to interventions cost-effective of Identification Abstract ¶ Email: [email protected] 2 place et Métabolisme,France Viala,Pierre34060, Montpellier * F-34060, France Montpellier 1 Affiliations Authors: Musclepreventionwastingand and Title: aging:experimental models, infiltrations, fatty Issue:Special Aspects Frailty” “Molecular and ofSarcopenia truclr dps tsu fr h aemdae ls o seea-uce ucin and function skeletal-muscle of loss age-mediated the for tissue adipose ntermuscular These authorscontributedThese work. equally to this Corresponding Author: Université de Montpellier, INRA, UMR 866 Dynamique Musculaire Dynamique 866 UMR INRA, Montpellier, de Université Author: Corresponding nvrié e otele, NA UR 6 Dnmqe uclie t Métabolisme, et Musculaire Dynamique 866 UMR INRA, Montpellier, de Université intermuscular adipose tissue in muscle wasting and aging and try to highlight new findings new highlight to tryand aging and wasting muscle in tissue adiposeintermuscular

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Page 1 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of a scientific a is She Montpellier). STAPS, the of member (UFR Sciences Sports of Faculty the in anatomy Chopard Angèle mu in interest special with conditions, pathological or nutrition) and (exercise physiological under regulation mass muscle on focused is work His University. Montpellier at DMEM 866 UMR Py Guillaume fatty of accumulation and development the in skeletalinfiltrations muscle, especiallyduring regeneration. studying currently is He exercise. during focused was work his his during First, (SMH). Sciences Movement Human of School Graduate the signaling and remodeling Pagano F. Allan strategi of development the in interest special with conditions, microgravity or pathological, aging), mainly focused been is research HisMontpellier). STAPS, Sciences(UFR Sports of Faculty thein Assistant Research has he (France), Delamarche Arlette Prof. and (Spain) Viña José Prof. of laboratories the in Ph.D. his receiving After (CNES). Agency Space French ” signaling Brioche Thomas Vitae BeExercise, Keywords: target therapeutic potential a discuss will we Finally, sarcopenia. and wasting muscle prevent methylbutyrate Issue:Special Aspects Frailty” “Molecular and ofSarcopenia principal investigator in space and microgravity experiments conducted under the aegis of aegis the under conducted experiments microgravity and space in investigator principal : : scleregeneration. es against muscleagainst es anddeconditioning studyinginvolvement the of stress. oxidative Master’s em n h UR 6 DE a Mnplir nvriy wt a rn fo the from grant a with University, Montpellier at DMEM 866 UMR the in team uce iue Sroei, irgaiy Itruclr dps tsu (IMAT) tissue adipose Intermuscular Microgravity, Sarcopenia, disuse, Muscle ta Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 , -hydroxy-beta-methylbutyrate(HMB) Ph.D., is Ph.D., “ is a Ph.D. student at the University of Montpellier (France) on on (France) Montpellier of University the at student Ph.D. a is is muscle remodeling and signaling and remodeling muscle on s currently is of a uce as euain ne pyilgcl eecs, urto, and nutrition, (exercise, physiological under regulation mass muscle program, on autophagy and protein turnover signaling in skeletal muscle skeletal in signaling turnover protein and autophagy on program, sarcopenia:glucose6-phosphate dehydrogenase. Professor at the University of Montpellier. She teaches physiology and physiology teaches She Montpellier. of University the at Professor Comment citer cedocument: a co ” team (INRA, UMR UMR (INRA, team ” supervisor of the of supervisor a ototrl eerhr n the on researcher postdoctoral

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Page 2 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of in and disuse chronic after restanalog. effects ofand to the relation its spaceflight bed deconditioning muscle skeletal of prevention and study the on mainly focused is research Her CNES). and (ESA agencies space French and European the Issue:Special Aspects Frailty” “Molecular and ofSarcopenia Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument:

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Page 3 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of 6. 3. 8. 7. 5. 4. wastingmuscle andaging 1. Issue:Special Aspects Frailty” “Molecular and ofSarcopenia 2. ferences 2.4. 5.2. 2.3. 6.4 6.2 6.1. 5.1. 2.2. 2.1. dehydrogenase 6.3 Re Acknowledgments Strategies against sarcopenia against Strategies sarcopenia an important of IMAT: factor and molecular skeletal muscle Cellular alterations of of sarcopeniaCharacteristics studiesTranslational approaches onskeletal for andexperimental models Introduction 6.3.3. 6.3.2. 6.3.1. 6.2.2. 6.1.3. 6.1.1. 6.3.4. 6.2.1. 6.1.4. 6.1.2. . . .

Cell models of muscle wasting How does fat infiltration occur sarcopenia? in Animal ground-based models of muscle disuse Exercise as most the effective strategy against sarcopenia fightThe against inactivity: realthe purpose Human ground-based models of muscle disuse Real microgravity experiments A potential therapeutic intarget sarcopenia: Glucose 6-phosphate Nutritional interventions: case the of HMB Hormone replacement therapies as a possible strategy

Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Effi HMB: HMB, whoare you? GH replacement therapy Exerc Exercise during aging improves protein balance Molec Testosterone replacement therapy Exerc Exerc ciency of HMB in various muscle ...... a very potent strategy against various muscle- ise during aging improves mitochondrial function and dynamics ise during aging stimulates SCs ise during aging decreases myonuclear apoptosis

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Page 4 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of 2008 al., diet, including Sayer etet (Derbre 2014; al., aging and itself the process diseases,physical inactivity, chronic sarcopenia, to contribute factors Multiple 2010). al., et Muscaritoli al., 2011; et Morley 2011; al., et Fielding 2010; al., et (Cruz-Jentoft sarcopenia called syndrome mass, pulmonary obstructive chronic (COPD). disease or diabetes, (cachexia), cancer like of consequences changes indirect pathological of case in deconditioning, secondary as or aging, and lifestyle, rest, bed immobilization, disuse, chronic as such conditions, environmental unfavorable of consequences direct primary of as case in defined deconditioning, be can deconditioning muscle Skeletal 2006). Attaix, and Ventadour 2015; al., et Pagano 2002; Stevenson, and Kandarian 2004; Kandarian, and Jackman 2005; mechanical in decrease a Conversely, Glass, 2013; Sandri, and (Bonaldo atrophy and deconditioning muscle to lead will constraints 1990). al., et Staron 2004a; Fulco, and Sartorelli positive a cause can environmental prot nutrition to or exercise, adaptations stimulation, in tissue increase muscle an Thus, into constraints. translate also can plasticity muscle Skeletal 2007). Thomas, 2005; al., et (Giresi sarcopenia as defined mass muscle in decrease natural a older: and 30 of age the by appears trend opposite The strength. and mass muscle in increase an with growth adolescent and childhood during observed first are adaptations resistance sufficient masshave must quality. and insulin and stocks), acids amino prot and glucose important most the contains muscle skeletal Moreover, 2012). Fielding, and (Reid balance and maintenance, posture living, daily 2012) Fielding, and (Reid person a expenditure enabling locomotion in role central energy a plays muscle Skeletal basal the of ~30% and weight body the Issue:Special Aspects Frailty” “Molecular and ofSarcopenia 1. ection (Brook et al., 2015). In order to ensure these essential functions, skeletal muscle skeletal functions, essential these ensure to order In 2015). al., et (Brook ection i aac ad nov msl yetoh adrifreet Crtne l, 1988; al., et (Cureton reinforcement and hypertrophy muscle involve and balance ein

n uce tegh ad n hscl efrac ad s considered is and performance physical in and strength, muscle in Skeletal muscle is the most abundant tissue in the human body representing ~40% of ~40% representing body human the in tissue abundant most the is muscle Skeletal Introduction Muscle deconditioning occurring with aging is characterized by a decrease in muscle muscle in decrease a by characterized is aging with occurring deconditioning Muscle muscle Substantial levels. different at itself expresses plasticity muscle Skeletal efrs mjr ucin n hroeei poess eeg spl (hs tissue (this supply energy processes, thermogenesis in function major a performs Topo, 07. u t sca, ehooia, n mdcl rges life progress, medical and technological, social, to Due 2007). Thompson, ; Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument:

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Page 5 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of aim is review present The wasting. muscle during pathways various these among crosstalk of extent the and molecules, signaling intracellular studies focused onfrom specificelucidating the contributionsoftranscriptional mechanisms, derived been mainly has muscle skeletal on hypodynamia and hypokinesia of effects the of muscle will data these and during 2002), al., et Stein 2007; al., et proteins Schiaffino 2000; al., et Fitts 2001; al., contractile et Chopard 2005; al., and structural, metabolic, deconditio of expression the comprehensive devise analysis ofmuscle wasting. to opportunities models,the togetherbringingexperimental ofseveral means by deciphered (e.g., used method invasive overcome To biopsies). the muscle and people, old healthy finding with difficulty the cost, high the to due undertake to hard is project a Such people. healthy old with people young development. and onset sarcopenia in involved pathways underlying the as well as mechanisms systemic and molecular, cellular, the understanding requires It challenge. health public major a is elderly the in performance physical and strength, muscle mass, muscle maintain to interventions Delm li daily of activities basic perform to inability progressive a fractures, and falls of risk increased an in resulting condition physical the of deterioration general to linked are costs healthcare American the to sarcopenia of cost total the example, for and, costs, health public the for catastrophic sarcopenia consideredis of increasing prevalence The 2004). al., (Janssenet likelysarcopenic are older and 65 age of womenand men of one-half to one-quarter that estimated currently (UN, 2050 by 22% to 2007) population the of 11% from worldwide double will people elderly of number the that projected is it Currently, population. societies,world the of aging global to western leading modern our in century 19th the since increasing been has expectancy Issue:Special Aspects Frailty” “Molecular and ofSarcopenia ving ls o idpnec fr h edry ad liaey dah Cu-etf, 2012; (Cruz-Jentoft, death ultimately, and elderly, the for independence of loss , nc e a. 20; odatr t l, 2006) al., et Goodpaster 2007; al., et onico . Inevitably, due to this aging population, prevalence of sarcopenia is growing, and it is it and growing, is sarcopenia of prevalence population, aging this to due Inevitably, . bnat ieaue led describes already literature Abundant healthyof comparison is research of standardgold mechanisms, the theseidentify To elhae ytm s prxmtl $84 ilo (ase e a. 2004) al., et (Janssen billion $18.4 approximately is system healthcare ig Bnlo n Snr, 03 Bice n LmieMrl 21; hpr et Chopard 2016; Lemoine-Morel, and Brioche 2013; Sandri, and (Bonaldo ning Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 be presented in the this review only briefly. To date, our understanding our date, To briefly. only review this the in presented Comment citer cedocument: th ese problems, muscle deconditioning processes have been have processes deconditioning muscle problems, ese

a uttd o msl aattos affecting adaptations muscle of multitude ed at addressing three main points. First, points. main three addressing at . Identification of cost-effective cost-effective of Identification

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Page 6 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of o hnig ees f tan Lce e a. 20a. hs te tde o aatto o the of adaptation microgravity 1 to from system, musculoskeletal on studies the Thus, 2004a). al., et (Lecker strain of levels changing to adaptation of feature common the share they pathways, molecular and cellular different via function and structure the in changes biological involve may spaceflight and aging Although 2009). Trappe, 2000; al., et (Fitts sarcopenia and osteoporosis age-related on research the agingand of space both effects travel. the to contribute metabolism oxidative impaired and resistance, insulin responses, immune events physiological involve to appear experiments microgravity and span, time long the is process aging the studying with difficulty greatest the Moreover, subjects. elderly in fractures and falls of prevention the to relevant are approaches Similar balance. postural and strength, endurance, muscle of preservation account into take must environments altered-gravity in function muscle maintain to required countermeasures of types the Furthermore, atrophy. studies process aging to substantially contribute to appear and weakness muscle into research the to time this at contribute studies spaceflight and models ground-based Various wasting. and sarcopenia. muscle wastingprevent and and therapies, hormone replacement exercise, which present part third The 2003). Narici, and Prampero di 1997a; al., et (Berg deconditioning muscle during keep aging, and wasting muscle in (IMAT), tissue adipose intermuscular called also infiltrations, experime w Issue:Special Aspects Frailty” “Molecular and ofSarcopenia 2003) e 2. any ou o aalbe xeietl oes novn cl, nml o human or animal, cell, involving models experimental available on focus mainly ing in mind that the loss of strength and power mostly exceeds the loss of muscle mass muscle of loss the exceeds mostly power and strength of loss the that mind in ing ua eprmna mdl fr tdig n dcpeig h poess f muscle of processes the deciphering and studying for models experimental human

. In the past decades, the scientific community validated several selected cell, animal, animal, cell, selected several validated community scientific the decades, past the In and agingwasting studiesskeletalon muscle Translational approaches experimentaland models for ned msl arpy n wans, eue cpct fr xrie unbalanced exercise, for capacity reduced weakness, and atrophy muscle Indeed, ng agi mimicking nts to study muscle wasting. The second part points out the role of fatty fatty of role the out points part second The wasting. muscle study to nts s Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 (Figure the main data on the efficiency and molecular and cellular mechanisms by by mechanisms cellular and molecular and efficiency the on data main the 1) Comment citer cedocument: . ascae cags ht ae lftm t dvlp Boo t al., et (Biolo develop to lifetime a take that changes -associated

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10 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of model, HU the in unaltered are are genes these of most immobilization denervation, during similarly regulated during perturbed genes most although that emphasized models, HU and denervation, immobilization, comparing analysis profiling transcript a describes which (2001), al. et Bodine by study The 2003). Falempin, and Picquet 2005; al., et Mueller 1999; al., et Cros 2013; al., et Chowdhury 2001; al., et Chopard 2001; al., et (Bodine experiments tail- in either weeks, 2 after ~40% by decreases example, for mass, muscle Soleus weeks). 2 (usually period same the within animals in pelvic-HU and tail-HU involving Holt Morey- 2013; al., et (Chowdhury system for harness allow the and to unloading, attached of isangle the mouse mobility, or rat a which to device the unit, housing the are model this of parameters crucial most The published. been have articles research hundred Several 2002) Globus, and Morey-Holton 1979; (Morey, weightlessness simulate to validated was and mid-1970s the in Center Research Ames (NASA) Administration Space and Aeronautics after denervation. observed those than less are muscles aging in observed damage skeletal-muscle of extent and severity rule, general a As 2001). al., et (Borisov death cellular to death nuclear from lead pathways which unclear remains it but aging, during and muscles denervated in both observed, are process the parallel, In 2000). al., et (Borisov collagen o amounts increased and microvasculature reduced signs: common some share muscles old and muscle denervated level, histological the At slower. loss the Thus, rats. 32-month-old (2001) al. et Carlson Moreover, 49 of decrease a showed denervation. of months 4 after (EDL) longus digitorum and mass of loss disproportional a revealed al. Carlson (1996) et by study The force. and mass muscle report usually investigators deconditioning, muscle of several in models As muscle. skeletal for consequences molecular the study and explore to used procedures experimental the denervation, increased with associated is age advancing because and context, this In identify. to difficult been always has and al., (Furunoet 1990), degradation protein accelerated Issue:Special Aspects Frailty” “Molecular and ofSarcopenia on and Globus, 2002). The skeletal muscle wasting of HU rats is comparable in studies in comparable is rats HU of wasting muscle skeletal The 2002). Globus, and on The rodent model of hindlimb unloading (HU) has been developed by the National the by developed been has (HU) unloading hindlimb of model rodent The a Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 9 rdcin n aiu ioerc otatl fre n h rt extensor rat the in force contractile isometric maximum in reduction 99% Comment citer cedocument: % of muscle mass and a a and mass muscle of es

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11 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of In 1998). al., et Wang 1997; al., et Tiao 1999; al., et Thompson 2005; Thissen, 2013b; al., et Schakman 2007; al., et(Klaude muscle wasting ofmodel vitro in an asstudies several in used and dexamethasone, involving experiments cell in reported disruptions Metabolic in observed also are models 2013a). animal experimental and humans in muscle al., skeletal atrophying et Schakman 2013; al., et Kuo 2014; al., a to attributable simply not ofgenes. set particular is and genes expressed differentially many great a reflects as Y below. presented such those conditions, atrophy whole-muscle of pathways phenotype signaling study distinctive to a model revealed suitable culture in myotubes of starvation hand, other 2004b) Fulco, and (Sartorelli expression mRNA and protein in changes few a least at cell cells PBS-treated 2005). These 2004). al., et al., (Sandri MAFbx ligase protein et ubiquitin the least at (Stevenson of activation showed atrophy rapid to leads L6) (C2C12, lines cell to (hours short-term of application simple the media, differentiation replenish to failure The 2004). al., et (Sandri atrophy whole-muscle of details molecular of identification for system a as used was cultured cells of Starvation developed. been have models culture cell several atrophy, muscle of details molecular the study To 2004b). Fulco, and Sartorelli 2004; al., et (Sandri pathway disease in inducers atrophy that of kinds all attribute to thus and 2004b) similar al., et (Lecker models expression differential show genes of subsets several above, cited conditions muscle-wasting in Indeed, event. triggering process the of these regardless mechanisms that suggesting 2004b), al., et (Lecker atrophy of types these for common is expression differential whose genes of subsets are there diseases, and 2003), al., et (Pattison immobilization 2003), al., et (Stevenson unloading fasting, by induced (Bodineare2001). upregulatedetal., atrophyin (muscle allF-box) threeofatrophy models MAFbx and RINGfinger(Muscle1) atrogenes,MuRF1 twothe timethatfirst forthe reported study this Nonetheless, models. these in observed are atrophy of rates similar though even Issue:Special Aspects Frailty” “Molecular and ofSarcopenia 2.4. culture models have been said to “mimic” atrophy in viv in atrophy “mimic” to said been have models culture t a be pooe ta wt vros ye o msl arpy sc a those as such atrophy, muscle of types various with that proposed been has It Glucocorticoids (GCs) Glucocorticoids

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12 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of cells, C2C12 with incubated When 2004). al., et Zhu 1987; Transforming 2014b). al., et Kimura growt 2007; al., et (Dehoux line cell C2C12 the in wasting TNF- as such cytokines leads and TNF- by the stimulated to is addition pathway In FoxO4 2008). the al., pathway, Akt-dependent et canonical Magee 1998; al., et Li 2004; al., et Cai 2010; Guttridge, at even UPS the of components various factor nuclear of activation via proteolysis, and apoptosis of induction and po a is α “ 2005) Thissen, 2013b; al., cultureet (Schakman cell muscle for used extensively been has atrophy inflammation-related atrophy, as such MuRF- atrogenes and several MAFbx, of FoxO1/3a, upregulation by mediated is UPS, the especially systems, 2005) Thissen, 2013b; al., et (Schakman systems lysosomal 25 by accompanied myotubes C2C12 myotubediameter ofreduction and L6 both in rates degradation protein in that 1999) al., et Thompson 2006; al., et Sultan 2004; al., et 10 from ranging concentrations by induced be to varied dexamethasone of concentration The wasting. muscle of mechanisms the identify to used been have lines cell (C2C12) mouse and (L6) rat on based myotubes dexamethasone-treated experiments, these Issue:Special Aspects Frailty” “Molecular and ofSarcopenia f ybat (le ad ohr, 97 ad a sprs dvso ad lc fso of fusion block and division suppress c satellite can and 1987) Boxhorn, and (Allen myoblasts of TGF- tissue that showed studies effects, apoptosis, differentiation, growth, fibrogenic the Besides 1992). al., et Shull 1990; (Massagué, cell inflammation and development, including processes, biological various TGF- 1990). (Massagué, activins and (BMPs) proteins morphogenic cachectin treatment with dexamethasone or corticosterone resulted in dose in resulted corticosterone or dexamethasone with treatment h factor h ehnsial, C at i atvto o te bqii poesm (P) n the and (UPS) proteasome ubiquitin the of activation via act GCs Mechanistically, tent trigger of muscle wasting in vitro and in vivo, through inhibition of myogenesis of inhibition through vivo, in and vitro in wasting muscle of trigger tent ells both in vitro and in vivo by suppressing myogenic factors (Allen and Boxhorn, and (Allen factors myogenic suppressing by vivo in and vitro in both ells to ” (Mirza et al., 2014a), can induce C2C12 atrophy when added to cell culture. TNF- culture. cell to added when atrophy C2C12 induce can 2014a), al., (Mirzaet MAFbx mRNA upregulation (Moylan et al., 2008) al., et (Moylan upregulation mRNA MAFbx Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 β 1 (TGF- 1 Comment citer cedocument: β1) belongs to a family of multifunctional cytokines including bone including cytokines multifunctional of family a to belongs β1) α plus plus α ong the studies, and the effects of dexamethasone were found were dexamethasone of effects the and studies, the among . nefrn (IFN)- interferon

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13 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of as reduced is plantaris and anterior, comp tibialis quadriceps, gastrocnemius, EDL, soleus, the of weight the rats), for age (middle months ~18 age at strain, the of regardless Usually, Brown 344 Norw Fischer 1993). (Hopp, months 30 and 18 between elderly considered are rats strain the on Depending sarcopenia. studying for useful particularly animals experimental 1988) al., et Lexell 2004; al., et Kimball 2013; al., et (Ibebunjo death to adulthood the from ~40% . 2000a) al., et (Frontera age of years 35 as early as start can and 60, age after year per 2.5% to 1.4% Lakatta,1988),and (Fleg 6% amounting between decade yearsto per 30 aging, ofage70 and 2012) al., et (Mitchell women in ~0.5% and men in year per ~1% of rate a at declines mass muscle years, and strength, physical rodents. muscle and inperformancehumans al., et 2010). Morley al., et Muscaritoli 2011; 2011; al., et Fielding 2010; al., et (Cruz-Jentoft performance physical poor fusio MAF ligases 2015) are cells these 2008); al., et (Baker accelerated-aging of model mouse hypomorphic BubR1 the 2016; al., et (Abrigo MAFbx Mend and MuRF-1 of expression protein increases and diameter Issue:Special Aspects Frailty” “Molecular and ofSarcopenia Kimball e Kimball 2013; al., et (Ibebunjo gastrocnemius the notably muscles, some in 60% reach can decrease this old), months (~30 animals old very In 2010). al., et Paturi 2004; al., et Kimball 2013; al., et (Ibebunjo but rats) in (~10%) age (old months age 24 age of at 40% to months 30% reach 18 to thereafter accelerates at small and slow relatively is decrease This 2010). al., et characterized by a subpopulation of muscle stem cells expressing p16Ink4a (Nozaki et al.,p16Ink4a (Nozakiet stemexpressingcells subpopulation characterizedofmuscle a by 3. n index (Nozakietal.,index n 2015). ay F1 hybrid and Wistar rats are the most popular most the are rats Wistar and hybrid F1 ay

ared to animals aged 6 or 12 months (Ibebunjo et al., 2013; Kimball et al., 2004; Paturi 2004; al., et Kimball 2013; al., et (Ibebunjo months 12 or 6 aged animals to ared ; this decrease can exceed 50% (Baumgartner et al., 1998)al.,et (Baumgartner 50% can exceed decrease this ; ubiquitin muscle-specific the of expression increased shows line cell modified This . ias et al., 2012). More recently, Nozaki et al. (2015) developed the C2C12 cell line from linecell C2C12 the developed (2015) al. et Nozaki recently, More 2012). al., et ias The three components of sarcopenia are low muscle mass, low muscle strength, and strength, muscle low mass, muscle low are sarcopenia of components three The Typically, in Typically, Characteristics of sarcopenia-related muscledeconditioning Characteristicsof sarcopenia-related In humans, it is accepted that aging is accompanied by a decrease in muscle mass by mass muscle in decrease a by accompanied is aging that accepted is it humans, In t al., t 2004). bx and MuRF-1, reduced expression of MyoD and myogenin, and a decreased decreased a and myogenin, and MyoD of expression reduced MuRF-1, and bx . Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Nevertheless, the decline of skeletal-muscle mass may accelerate along with along accelerate may mass skeletal-muscle of decline the Nevertheless, humans, muscle mass remains stable during early life, but after age ~50 age after but life, early during stable remains mass muscle humans, Comment citer cedocument: Table 1 Table

presents methodologies used to assess muscle mass, muscle assess to used methodologies presents rat strains for studies on sarcopenia. on studies for strains

. Rodents, especially rats, are rats,Rodents,especially 14 , Page

14 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of 2011; of diagnosis al., for value cutoff the on consensus no et still is there however, 2011); al., et Fielding Morley 2010; al., et (Cruz-Jentoft sarcopenia of diagnosis for performance forcebut maximal EDL, afterthe decreased 24monthssoleus. in the Faulkner, and 1988; (Brooks EDL and gastrocnemius, soleus, the in months 36 and 32 between observed generally is force 344 maximal in Fisher decrease a this mice, in aged and Thus, hybrid of F1 Norway rodent. Brown onset the of the age and but strain the rodents, on in depend to observed seems phenomenon were results Similar 2001). al., 2000b; et al., et Hughes Frontera 1986; al., et (Aniansson years 70 and 60 ages between extensors by reduction a revealed studies longitudinal Indeed, years. 70 and 60 between especially accelerated be to seems muscle strength Decreased 1980). al., et Murray 1985; al., et (Murray years 90 over aged subjects 1984) al., et McDonagh 1993; Harries, and (Bassey flexors wrist and shoulder as such groups muscle other with observed were results 20- between 20-40% by decreases strength peak the average, On 2003). (Doherty, importance 2010) al., et (Cruz-Jentoft person affected the of autonomy for important are consequences functional (AnianssonIIaet al., Coggan al., to type fibers1986; 1992)et compared type IIx fiber the in observed are reductions greater fibers, muscle II type Among 1988) al., et Lexell 1978; al., et Larsson 2000; al., et (Hikida size their in 60% to 20% from be to appear fibers II type fast Indeed, similarly. aging with associated mass fibers muscle of types all affect not does Atrophy 1988). muscleal., et Lexell 1986; al., et (Aniansson of decrease the in implicated also is area) sectional 1992) years 80 al., and et 50 (Aniansson between reported is 40% to 30% of reduction a age, of years 50 and 24 1985) al., et Young type and fiber I type both affecting fibers Issue:Special Aspects Frailty” “Molecular and ofSarcopenia 30 and 70 and Ryall et al., 2007; Thomas et al., 2010). In Wistar rats, no difference was observed in observed was difference no rats, Wistar In 2010). al., et Thomas 2007; al., et Ryall The decrease in muscle strength is a key diagnostic criterion diagnostic key a is strength muscle in decrease The at pe i nw h rcmedd aaee fr seset f physical of assessment for parameter recommended the now is speed Gait muscle of loss a to due mainly is mass muscle in decrease age-related the humans, In . Muscle strength of the knee extensors should be consider be should extensors knee the of strength Muscle Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 – 80 years (Larsson et al., 1979; Murray et al., 1985; Young et al., 1985). Similar 1985). al., et Young 1985; al., et Murray 1979; al., et (Larsson years 80 . Although a decrease by only 5% in the number of fibers occurs between occurs fibers of number the in 5% only by decrease a Although Comment citer cedocument: . oehls, toh o msl fbr (euto o ter cross- their of (reduction fibers muscle of atrophy Nonetheless, % to 40% in the peak strength of the knee and shoulder and knee the of strength peak the in 40% to 30%

II fiber (Aniansson et al., 1986; Lexell et al., 1988; al., et Lexell 1986; al., et (Aniansson fiber . rae rdcin (0) r sil eotd in reported still are (50%) reductions Greater the most affected by aging, with a declin a with aging, by affected most

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15 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of ratsyoungetal., (Derbre to 2012). compared physical shown Decreased also is test). rodents (tightrope old tightrope in performance a or Test) Balance (Beam beam narrow measur who (2008), al. et Emerich and (2007) al. (23 rodents old in coordination and balance the are tests numerous but animals, available old in performance physical in decrease the evaluate with to how on consumption consensus no oxygen is there rodents, maximal In 2004). al., and et (Short restinghumans in age both advancing in decrease a by revealed also is performanc physical Poor defined. be to needs sarcopenia for point cutoff the but settings 2007) al., et (Bean subject the of weight the to normalized is and climbing of rate the and steps the of height the to relation in calculated climb must subject The 2007). al., et (Bean limbs lower the of power estimates clinically used when SCPT the Finally, 5 to 1 of scale a on assessed is that balance dynamic the of estimation for allows method This sit. to back come and around, short turn distance, a walkchair, a standfromup must subject test a is TUG The practice. clinical for and research for measure standard a is SPPB 2000). al., et (Guralnik sarcopenia the all on scores the of subt sum the and score, performance a yields event Each 1994). al., feet wit balanc g timed the tests), physical short of battery (standardized (SPPB) Battery Performance Physical Short the are popular most The acceptable. also are people elderly for specifically designed tests Other research. and practice clinical in used second easily the be in can speed m/s Gait 0.8 2009). than al., less et (Cesari and case first the in m/s 1 than less speed a as defined 2010) al., et (Cruz-Jentoft test 4-meter the or 2011) al., et Morley 2011; al., et (Fielding test 6-meter the by evaluated usually is speed Gait sarcopenia. Issue:Special Aspects Frailty” “Molecular and ofSarcopenia (Mathias et al., 1986). A score below 3 means probable sarcopenia (Mathias et al., 1986) al., et (Mathias sarcopenia probable means 3 below score A 1986). al., et (Mathias h the feet together in side- in together feet the h , ests characterizes overall performance. A score below 8/12 points to probable probable to points 8/12 below score A performance. overall characterizes ests and time to rise from a chair and return to the seated position five times (Guralnik et (Guralnik times five position seated the to return and chair a from rise to time and , at pe, strength, speed, gait e, et (Table 1) (Table - up Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 adg (U) o te ti cib oe ts (CT. h SP evaluates SPPB The (SCPT). test power climb stair the or (TUG), -and-go . Very few data are available on old rodents old on available are data few Very . Comment citer cedocument: 10 of steps as soon as possible. The power of the lower limbs is then is limbs lower the of power The possible. as soon as steps the time required to perform a series of basic motor tasks. The tasks. motor basic of series a perform to required time the n edrne y xmnn a idvda’ aiiyt stand to ability individual’s an examining by endurance and by -side, semitandem, and tandem positions, time to walk 8 walk to time positions, tandem and semitandem, -side,

by . – erae edrne aaiy n l rats old in capacity endurance decreased hs et a b ueu i sm research some in useful be may test This 24 months) have been reported by Altun et Altun by reported been have months) 24 ed th e time that that time e .

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16 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of 2004) and resting both in decrease a by judging bioenergetics, in and decline a is dysfunction mitochondrial Konopka 2013; age-associated of consequence al., major One et 2013). al., et (Calvani Marzetti 2013; Nair, authors Sreekumaran numerous by sarcopenia of cause central the as viewed are functions mitochondrial of alterations age-related that surprising not is pathways, death cell and catabolic several of regulation and homeostasis, redox provision, animals aged in unchanged is and Adams,2006; (Haddad Thompson 2006). etal., muscle in expression protein its and 2000) al., et (Hasten humans in aging by affected not is synthesis actin because specific be to appears decade proteins per 1% and 3% by decline levels protein respect IIx and IIa MyHC why and 2006) al., et Thompson 2006; Adams, and (Haddad animals young to compared as reduced is animals old of muscle the in content protein MyHC why part in explain may This 2005). al., et Short 2001;al., et (Balagopal isoforms IIx MyHC and IIa MyHC e.g., aging, during decrease isoforms different of mRNA of amounts the because transcription its in decrease a to due least at is and (Gumucio caspases) and calpains (i.e., proteases of activation calcium-dependent and UPS via proteolysis increased their and 2006) Adams, and Haddad 2005; al., et Cuthbertson 1997; al., et (Balagopal synthesis proteins mitochondrial and MyHC) chain: heavy myosin (especially myofibrillar of reduction the by characterized 2009) al., et (Combaret turnover prot the as well andsarcopenia onset development.in pathways involved as mechanisms systemic and cellular the understanding requires sarcopenia 5 in part discussedbe will point This 2000). al., et Goodpaster 2014; al., et (Addison infiltrations IMAT in increase Issue:Special Aspects Frailty” “Molecular and ofSarcopenia 4. ein degradation systems. It is well established that sarcopenia involves negative protein negative involves sarcopenia that established well is It systems. degradation ein Mendias, 2013; Konopka and Sreekumaran Nair, 2013) Nair, Sreekumaran and Konopka 2013; Mendias, aia oye cnupin ( consumption oxygen maximal

and mice (Lee et al., 2010) and by decreased endurance capacity in old rats compared rats old in capacity endurance decreased by and 2010) al., et (Lee mice and The development of effective treatments or prophylactic measures against against measures prophylactic or treatments effective of development The ie te ia fntos are ot y iohnra n h cnet f energy of context the in mitochondria by out carried functions vital the Given and synthesis protein between act balancing a mostly is mass muscle Maintaining an by characterized also is muscle deconditioned) generally more (and Sarcopenic Cellular and molecular alterations of skeletal andmuscleCellular of molecularalterations vl, n uas Sot t l, 2005) al., et (Short humans in ively, Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 .

Comment citer cedocument:

O 2 max . wt avnig g i hmn (hr e al., et (Short humans in age advancing with ) hs erae n h snhss f myofibrillar of synthesis the in decrease This .

The decrease in MyHC synthesis MyHC in decrease The

the 17 it , Page

17 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of on focused Studies 2004). al., et (Lowe activity ATPase myosin decreased and 2000), al., et con of modifications posttranslational e.g., results, these explain to proposed are mechanisms 1999) Brown, and Thompson 2009; Thompson, 1998; al., et Renganathan 2000; al., et (Gonzalez (i.e., phenomenon. this fibers muscle isolated of strength specific that shown in have studies animal from data Indeed, involved factor only the considered not is it aging, during strength fibers satellite muscle by (SCs cells sarcopenia in nuclei new during of incorporation limiting capacity regeneration observed muscle in alterations efficiency transcriptional by worsened probably is phenomenon This 2010). in al., et Roberts 2005; al., et (Cuthbertson decrease the in involved 2010; al., et Kovacheva likely is fragmentation this 2010); al., et 2008; Wohlgemuth 2006; al., et Siu 2012b; al., et Marzetti al., et (Braga sarcopenia of development the thus aging, paralleling of course the in muscle skeletal in increases fragmentation DNA apoptotic of extent the that that revealed have studies numerous Moreover, 2012b). al., et (Marzetti persons observation the by older supported in volume muscle reduced and speed walking slow is with correlates signaling apoptotic notion This deconditioning. muscle and associated 2009) al., et Snijders sarcopenia- in involved be to believed are 2011;2012a) al., et (Marzetti apoptosis of exacerbation (Hikida, regeneration muscle for 2009) capacity al., et Decreased Snijders 2012a; al., et Marzetti 2011; (Hikida, mass muscle of maintenance (Marzettimitochondria etal., of 2013). control quality defective and (mtDNA), DNA mitochondrial of) depletion (and/or to damage and species nitrogen and oxygen reactive of production involving cycle vicious a of result the is which 2009), al., et Vina 2013; al., et (Calvani functions and numbers mitochondrial 2008) (Chabiet al., increase inin old rats withmuscle associated an fatigability adultsare and older in 2010) al., et (Safdar strength isometric maximal and 2013), al., et (Coen capacity walking reduced with correlate to shown been have muscle skeletal of energetics mitochondrial in perturbations Moreover, 2012). al., et (Derbre rats young to Issue:Special Aspects Frailty” “Molecular and ofSarcopenia tractile proteins (Lowe et al., 2001), decoupling of complex excitation-contraction (Wang excitation-contraction complex of decoupling 2001), al., et (Lowe proteins tractile oc nraie t te rs-etoa ae o te ie) lo erae wt age with decreases also fiber) the of area cross-sectional the to normalized force bt otaitr rsls ae en eotd o (lfi e a. 21) Several 2011). al., et (Claflin too reported been have results contradictory but , in reduction a to related is muscle sarcopenic the of failure bioenergetic The . lhuh kltl uce toh cnrbts usatal t te os f muscle of loss the to substantially contributes atrophy muscle skeletal Although the involvedregeneration equilibrium and processesalso is in between apoptosis The Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument: ).

This point will be addressed in part 5.2. pointwill This beaddressedin part 5.2.

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18 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of fat describe to first the was (1965) Aherne knowledge, our To others. many among mu in increase an and 2015), al., et of Zampieri 2014; al., et Rivas dysregulation 2014; al., et (McGregor microRNAs 2015), al., et Piasecki 2007; al., et (Edstrom aberrations neuromuscular (e.g., cytokines proinflammatory of production increased 2013), Malmstrom, and Morley 2015; [IGF- 1 factor growth like insulin [GH], hormone growth (e.g., hormones anabolic of release the in decrease a including factors upstream numerous in wellreductionduringreviewedPiasecki asal. agingstrength by muscle et (2015). involved also are neurons motor of loss and units motor of loss a as such impairments 2008) al., et (Jimenez-Moreno tissue muscle rodent aged in decreased muscle is of changes age-associated in maxim the Thus, properties. contractile coupling excitation-contraction of involvement 2004) al., et Lowe 2001; al., et also is (Lowe filaments strength actin to bind that specific heads myosin of fraction in the in reduction a decrease by explained the that shown have fibers muscle permeabilized Issue:Special Aspects Frailty” “Molecular and ofSarcopenia coai t l, 05 Uzm e a. 21b. hs fty nitain ae el nw t be to sarcopenia, even or cachexia, COPD, myopathies,diabetes, conditions: many with known associated well are infiltrations fatty These 2014b). al., et Uezumi 2015; al., et linke Sciorati are accumulation 2010; al., et Marcus 2014; and al., et (Addison regeneration perturbed even and deconditioning, increase its muscle, skeletal human healthy of part variable a be may IMAT Although 2009). al., et Vettor 2012; al., et be not should IMAT Karampinos 2014; al., groups; et (Addison accumulation muscletriglyceride intramyocellular with confused between and fibers muscle the between deposition located adipocyte as defined first be can IMAT strength. muscle of variable loss independent the additional explaining an be may IMAT or infiltrations Fatty 2003). Narici, and Prampero di 1997a; al., et (Berg inactivity after observed mass muscle of loss the exceeds and Jackson 2011; McArdle,2009; Ji, 2007). 5. interleukin 6 and TNF- and 6 interleukin

scle oxidative stress (Brioche and Lemoine-Morel, 2016; Derbre et al., 2014; Jackson, 2014; al., et Derbre 2016; Lemoine-Morel, and (Brioche stress oxidative scle hs mcaim cnrbt t te ne o sroei ad r afce by affected are and sarcopenia of onset the to contribute mechanisms These There is now a growing body of evidence that the loss of strength and power mostly mostly power and strength of loss the that evidence of body growing a now is There IMAT: an importantan factorIMAT: ofsarcopenia Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument: α ) (Lee et al., 2007), insulin resistance (Walrand et al., 2011), 2011), al., et (Walrand resistance insulin 2007), al., et (Lee ) . The research on isolated intact muscle fibers revealed the revealed fibers muscle intact isolated on research The

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19 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of a with tests, stands chair repeated corre and walk 6-meter the on performance decreased performance and strength muscle fact, In 2002). both al., et Visser 2001; of al., et (Goodpaster loss the and accumulation IMAT of degree the between correlation a demonstrated cohort, elderly same the on performed studies, Two function. muscle and IMAT of levelsbetween relation evaluatedthe studies Subsequent decrease (1989 recen more or and tomography, computed 1989) using al., 2004) al., et et Song Rice 1999; Nicklas, 1983; and (Ryan al., women et (Borkan men old in infiltrations fatty larger showed already have papers old relatively some and 2002) 2014;al., et al., Kirkland 2000; et al., et (Addison Goodpaster age with strongly increase levels IMAT that known well been long 2009 al., accumulation et (Delmonico IMAT insulin-sensitivity and strength, in muscle mass, muscle increase in decrease a an matches that demonstrated have studies numerous Indeed, (FAPs). called population fibroadipogenicprogenitors in age, advancing with development IMAT for responsible possibly players cellular some highlight to try also will We countermeasure. a as activity physical increasing of role major the and function, muscle this around expand to continue subje certainly will knowledge scientific and year, after year 1991; al., et Kelley 1988) 1976; al., et al., Nordal et Kannan 1970; (Birkbeck, studies other by followed was report this and infant, newborn a in muscle, skeletal including tissues, various in infiltration Issue:Special Aspects Frailty” “Molecular and ofSarcopenia shown that IMAT infiltration into the mid-thigh muscle remains an independentriskof an factor remains muscle IMATinfiltrationinto mid-thigh that the shown In accumulation. IMAT sarcopenia: of component important new a identify to helped have studies these Altogether, development. IMAT matches aging with strength muscle of loss the that confirmed (2009) al. et Delmonico 5.1. ain ewe IA lvl ad efrac o bt tss Later, tests. both on performance and levels IMAT between lation ct. This part of the review is focus is review the of part This ct. l, antc eoac iaig To tde, okn t l (93 ad ie t al. et Rice and (1983) al. et Borkan studies, Two imaging. resonance magnetic tly, ), were the first to demonstrate fatty infiltrations with aging accompanied by by accompanied aging with infiltrations fatty demonstrate to first the were ), The literature highlights a correlation between IMAT levels and muscle function. function. muscle and levels IMAT between correlation a highlights literature The

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21 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of l the of disruption 2001; Diehl, and (Koteish aging with acids of fatty metabolize to ability decreased a in pathway role possible a highlighted They aging. during accumulation knowledge, our To understood. arelifestylepoorly sedentary ora sarcopenia infiltrationsduring tofatty leading overall adults. health of older and function muscle affecting both accumulation, IMAT and sarcopenia sedentary to leading progressive lifestyle the combat to order in elderly the train to way effective most the define precisely to needed are studies Further aging. during accumulation and development an reveal even (or of stabilization to in activity physical increasing of appear role important studies these Altogether, duration. and intensity, its used, exercise oftypeassociated race,even the age diseases and or their theof participants, the to relation a be go also may elderly the among intervention exercise an after content IMAT in no increase demonstrating studies though even 2008), al., et Walts 2011; al., et al., Santanasto et 2007; Prior 2010; al., et Ku 2012; al., et Jung 2009; al., et (Christiansen program exercise adults.older activityamong physical are sarcopenia in observed alterations muscular some that notion the strengthen studies two last The aging. with amount IMAT in increase any or mass muscle lean of loss any exhibit not do they that showed week, per on (2011) al. Wroblewski by et resistance aninteresting exerciseretraining Lastly, study session. a after levels IMAT in decrease a by followed session detraining a after elderly the among 2015) al., et (Nicklas adults older obese and overweight in training resistance moderate of months 5 after area IMAT the in decrease a shown has study recent A 2014). al., et (Jacobs falls to prone people older in intervention exercise shorter but intensive more a by or 2014) al., et (Gallagher diabetes 2 type with patients obese and overweight in intervention diet-and-moderate-exercise year 1- a by aging with IMAT in increase an prevented also studies Two 2008). al., et (Durheim Issue:Special Aspects Frailty” “Molecular and ofSarcopenia drsl.Teedsrpniscnb xlie rmamtoooia on fve in view of point methodological a from explained be can discrepancies These result. od old elite athletes, trained for fitness and sports competitions at least four or five times five or four least at competitions sports and fitness for trained athletes, elite old 5.2. Even if IMAT development and accumulation will be studied more, the mechanisms the more, studied be will accumulation and development IMAT if Even ueos tde as fie t dtc ay erae n MT otn atr an after content IMAT in decrease any detect to failed also studies Numerous

How does fat How infiltrationsarcopenia? occur in Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 a review by Kirkland et al. (2002) was the first to give some clues to IMAT to clues some give to first thewas (2002) al. et Kirkland by review Comment citer cedocument: . Taaffe et al. (2009) also observed an increase in IMAT content IMAT in increase an observed also (2009) al. et Taaffe

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22 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of cell the for receptor factor growth platelet-derived positive marker surface are which FAPs, These FAPs. called MSCs the including progenitors, age.advancing with 2009) al., et Vettor 2015; al., et (Sciorati reviews other in discussed already as transdifferentiation or sarcopenia in function SC on elaborate not will review Our studies. these in probed argue authors those and age, advancing withfunction SC on studies among discrepanciesof source main the as heterogeneity SC of importance the highlights also (2015) Munoz-Canoves and Brack by review The aging. during function both SC detail influence that precisely factors intrinsic and and 2015) extrinsic al., et Sousa-Victor 2015; al., et Colla La 2015; Canoves, Munoz- and Brack 2015; al., et (Blau subject this on research recent the discussed already 2014). al., et Sousa-Victor 2014; al., et Price 2014; al., et Cosgrove 2012; al., et Chakkalakal 2014; al., et (Bernet sarcopenia in SC- alterations specific confirmed also have tools, isolation/purification SC powerful more involving studies, newer However, 2011). al., et Villeda 1983; Harrison, 2005; al., et Conboy 1989; Faulkner, extrinsic/microenvironment to attributed largely be may aging with grafting function SC muscle whole-muscle in decline the and that demonstrated parabiosis have experiments on based studies Numerous 1988). Sadeh, 2002; al., et Renault 1997; al., et Marsh 2004; al., et Gallegly 2012; al., et (Collins-Hooper capacity regenerative in decrease expected the with concomitant 2013) al., et Suetta 1982; Lipton, of capacity proliferation development impaired with associated preferential is the with exactly coincides sarcopenia which 2014), al., 2007; al., et et Verdijk 2012; Verdijk al., et (Verdijk fibers muscle II type of lamina basal the under 2014) al., et Verdijk al.,2004; al., et Sajko 2002; et Renault 2004; al., et (Kadi declines then and 2000) al., et Roth 2006; al., et (Dreyer (MSCs).cells pointed also and 2001) al., et Wang Issue:Special Aspects Frailty” “Molecular and ofSarcopenia but will instead discuss the potential role of FAPs in IMAT accumulation in conjunction in accumulation IMAT in FAPs of rolepotential the discuss instead will but ht itnt C ust ae ifrnily estv t etisc n itisc factors intrinsic and extrinsic to sensitive differentially are subsets SC distinct that The muscular environment contains various populations of tissue-resident tissue-resident of populations various contains environment muscular The age of years ~70 until maintained is pool SC the that appears it SCs, Concerning in the fast-twitch type of muscle. It is also important to note that advancing age advancing that note to important also is It muscle. of type fast-twitch the in Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument:

to potential involvement of SCs and mesenchymal stem stem mesenchymal and SCs of involvement potential . There is a specific decline in SC content located content SC in decline specific a is There al atr (rc e a. 20; alo and Carlson 2007; al., et (Brack factors of C (oby t l,20; cut and Schultz 2003; al., et (Conboy SCs 

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23 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of the be can FAPs that fact the hand, other the on and 1995), al., et Simoneau 1999; Nicklas, and Ryan 1997; al., et Goodpaster 2000; al., et Goodpaster 1999; al., et (Goodpaster obesity and correlations the betw hand, one the on support, studies These 2015). al., et two Laurens 2015; Moreover, al., 2015). et (Arrighi al., resistant insulin are et adipocytes skeletal-muscle-FAP-derived Farup that demonstrated 2015; al., et (Blau IMAT the sarcopenia, highlights in literature FAPs of role the characterize to conducted been has study no though precursors adipocyte muscle-resident of characterization and better 2010) for al., allows et Uezumi 2010; 2010; al., et al., Pisani 2015; et al., (Joeet Pagano 2013; used al., et commonly Lukjanenko is regeneration of model glycerol the model, mouse experimental an in accumulation and development IMAT investigate to order In IMAT. of accumulation to lead FAPs case, this in 2000), al., et Heslop 1983; al., et (Blau content SC in and/or adipose into 2011) al., et Uezumi 2014a; al., differentiate et (Uezumi tissue fibrous and proliferate FAPs dystrophy, muscular as such conditions, Duchenne pathological or disuse muscle In 2015). al., et Lemos 2010; al., et Joe SC-mediated 2013; al., supportet (Heredia adipocytes and into differentiating without fibers, regeneration muscle muscle efficient necrotic of phagocytosis in participate after injury, quickly proliferate to able are FAPs muscle. skeletal in population cell stem studied Issue:Special Aspects Frailty” “Molecular and ofSarcopenia and further signaling toward FAPs, promoting differentiation.signalingtoward furthertheir and adipocytic neutrophil-induced defective a indicate may (2013), al. et Heredia of those al. et Butcher show Indeed, (2001) inflammation. including systems numerous of deregulation with associated are aging and regeneration Interestingly, survival. their promotes macrophages) TGF- whereas apoptosis, FAP provokes macrophages M1 by released TNF- between balance the of effect crucial the showed also (2015) al. et Lemos by study A 2015). al., et Sciorati 2014; advanc recent summarized excellentlyreviews various and regeneration, muscle efficient in systems main stem cell population implicated in sarcopenia-related IMATdevelopment.mainstemcell population implicatedinsarcopenia-related e IA acmlto adte eraei isln estvt bevddrn aging during observed sensitivity insulin in decrease the and accumulation IMAT een es in this field (Aurora and Olson, 2014; Madaro and Bouche, 2014; Maffioletti et al., et Maffioletti 2014; Bouche, and Madaro 2014; Olson, and (Aurora field this in es The recent literature underscores the critical role of the immune and inflammatory and immune the of role critical the underscores literature recent The ed Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 alteration of neutrophil function with aging, and these results, in light of of light in results, these and aging, with function neutrophil of alteration a osbe motn fnto o FP i aerltd eeomn of development age-related in FAPs of function important possible Comment citer cedocument: α and TGF and α

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24 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of lineage. not wasstudy that in isolated population the that however, note, to important is It aging. during changes environmental by influenced highly are FAPs that reveal studies these altogether also but mice mdx 2014) young from FAPs of promotes unexpectedly potential adipogenic the suppresses not only HDACi, with again intervention, epigenetic an that showed study Another mice. mdx inas young inabilityeffective old mdxtobeas HDACi ofin the treatment demonstrated mice also they However, 2013). al., et (Mozzetta differentiation SC support still thus and HDACi next They 2006). show al., certainly et (Minetti muscle, expression follistatin skeletal in increase an of by part recovery in mediated morphological and functional a promotes mice show first researchers These cycles). lesion-regeneration muscle permanent by (characterized mice mdx dystrophin-deficient on (HDACi) inhibitors discussed themodulate ofFAPsbelow. fate aging willandduring be these during in discussed accumulation FAPs of levels muscle the and development IMAT TGF- upregulationof The sarcopenia. to leading differentiation adipocytic TNF- between overlap possible the and deregulation inflammatory the Therefore, 2013). al., et Merritt 1993; al., et Fagiolo show defective demonstrated (2006) al. regulat et Przybyla regeneration. muscle during production TNF- of transition temporal Issue:Special Aspects Frailty” “Molecular and ofSarcopenia this this 2013) al., et Judson 2013; al., et (Boppart pericytes 1 type even or (SP), cells population side only purified FAPs: it may contain other populations such as PW1 interstitial cells (PICs), cells interstitial PW1 as such populations other contain may it FAPs: purified only methodological point point methodological ed ed are unpublished observations. Nevertheless, some other molecular pathways can also can pathways molecular other some Nevertheless, observations. unpublished are I cnrs, As rm l mx ie al o dp a ygnc hntp, and phenotype, myogenic a adopt to fail mice mdx old from FAPs contrast, In . o o msl mcohg fnto wt avnig g, n sm suis also studies some and age, advancing with function macrophage muscle of ion Numerous studies by the same group evaluated the effect of histone deacetylase deacetylase histone of effect the evaluated group same the by studies Numerous A that in young mdx mice, FAPs are sensitive to adipogenesis inhibition mediated by mediated inhibition adipogenesis to sensitive are FAPs mice, mdx young in that TNF- both increasein an study by Lemos et al. (2015) also elegantly demonstrated the precise and crucial and precise the demonstrated elegantly also (2015) al. et Lemos by study Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument: FAP may s’ α myogenic lineage (Faralli and Dilworth, 2014; Saccone et al., et Saccone 2014; Dilworth, and (Faralli lineage myogenic xli te nxetd eeomn aog h myogenic the along development unexpected the explain ad TGF and α α and TGF and α ponlmaoy t TGF- to (proinflammatory)

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25 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of age. advancing FAPs behind mechanism potential another reveal 2015), findings these al., et (Sciorati recently group same the by reviewed already was mechanism This adipocytes. into differentiation their of inhibition through fate FAP regulates NO that 2012) al., et Samengo 2012; al., et and IMATdevelopmentsignaling sarcopenia. during Wntof deregulation age-related underlying Furthermechanisms the elucidate to needed are studies direction. same the in vary all not will aging proteins Wnt to of related levels expression when because especially complex, particularly Wnt be to The appears accumulation. pathway IMAT signaling promoting genes adipogenic key of expression signaling Wnt10b increases altered aging, during that concluded they and Wnt10b, on particularly 2008) al., et Zaragosi 2007; al., et Shang 2000; al., et fateRoss 2003; al., et Moldes myogenic 2012; al., et Chung 2012; their al., et Brunt 2002; al., of et (Bennett promotion by accompanied adipocytes into differentiation MSC skeletalaged muscle. in FAPs in signalingpathway Notchthe of function studiestheconcerningare thereno Nevertheless, heart. adult the in repair cardiac and development fibrosis between balance the controls 2014) al., and progenitors cardiac et mesenchymal in mechanisms key Nemir regulates thereby signaling Notch 2008; al., et (Croquelois fibrosis of development abnormal to leads research addition, In aging. 2008; of entry spontaneous al., the explain may and 2009) et al., et Carlson Carlson 2010; Kadesch, and (Buas aging during TGF- upregulated Interestingly, inhibitor Notch 2005). al., et Conboy proliferation 2003; al., impaired et (Conboy in failure regeneration results response an signaling aging, During Notch 2012). al., et attenuated Wen 2011; al., et Pellegrinet 2012; al., et al., Mourikis et Conboy 2003; 2012; al., et (Bjornson injury after proliferation their of promotion as well du Issue:Special Aspects Frailty” “Molecular and ofSarcopenia ring aging. This pathway is a major one implicated in the maintenance of SC quiescence asquiescence SC of maintenance the in implicated one major a is pathway This aging. ring , and further research is clearly needed to identify a highly possible role of this pathway this of role possible highly a identify to needed clearly is research further and Aging is also linked to altered synthesis of nitric oxide (NO) in skeletal muscle (Nyberg muscle skeletal in (NO) oxide nitric of synthesis altered to linked also is Aging of inhibition the in signaling Wnt of role major a shown already have studies of Plenty en FAP-driv in involved be also may pathway signaling Notch The Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument: ha s demonstrated that altered Notch signaling in the adult heart adult the in signaling Notch altered that demonstrated s

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26 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of resistancein participation preclude can diseasethat cardiovascularunstable of forms certain or 2011) Hinman, and (Bennell osteoarthritis severe to moderate as such comorbidities or have nonambulatory are citizens senior many addition, In persons. most among of motivation lack the by hampered is intervention an . 2012) such of Bai, implementation and large-scale However, Wang 2011; al., et Pillard 2013; Serra-Rexach, and (Montero-Fernandez sarcopenia against strategy perfect the be to appears Exercise effects. side possible fewest would and sarcopenia of components three the on act would strategy perfect The is elderly the in performance physical and strength, accumu Notch, Wnt, HDAC, including pathways signaling many that showed We players. cellular some to them linking by aging and FAPs concerning clues new emphasize to tried we characteristics. that, After training the on depending elderly the in review accumulation IMAT next even in) (or decrease of We stabilization in activity inactivity. physical increasing of to role major the linked demonstrating closely new is this that factor emphasized important and sarcopenia during accumulation IMAT well-known the now described first We function. skeletal-muscle of loss age-mediated the in IMAT of role Lee2013). etal., 2013; function significant perform also to seems factor growth this though even FAPs on FGF-2 likely of effect the on conducted most been have then and 2012) al., et cycle, (Chakkalakal aging cell during observed the SCs of loss enter the to to contributes SCs driving quiescence, cell stem of loss a induces mechanism This 1. Sprouty inhibitor its of expression decreased to due age, with increases expression FGF-2 regeneration. muscle skeletal of impairment age-related in role Issue:Special Aspects Frailty” “Molecular and ofSarcopenia aging 6. , and influence, the stemcellof the nicheregulating IMAT development.

Finally, the fibroblast growth factor 2 protein (FGF-2) seems to also play an important an play also to seems (FGF-2) protein 2 factor growth fibroblast the Finally, NO Identification of cost-effective interventions to maintain muscle mass, muscle muscle mass, muscle maintain to interventions cost-effective of Identification In conclusion, this part of the review highlighted the increasing recognition of the the of recognition increasing the highlighted review the of part this conclusion, In Strategies against sarcopenia Strategiesagainstsarcopenia ain W ae ofdn ta nw tde wl srnte te ik aog FAPs, among links the strengthen will studies new that confident are We lation. ad G- my e mlctd n gn-nue IA dvlpet and development IMAT aging-induced in implicated be may FGF-2 and , Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument:

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28 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of that shown been has rpS6 it and hand, mTOR other the in On increase 2009). an al., et with (Chale-Rush conjunction phosphorylation in animals aged in weight plantaris increases days 28 for gastrocnemius the of from ablation bilateral by obtained induced overload muscle Data (activation). phosphorylation rpS6 hyper and with p70S6K, associated accretion Akt, protein muscle increased substantial and strength, muscle in increase an increase), area sectional (cross hypertrophy muscle to leads 1RM) of 80% week, per days (12 exercise resistance that people elderly in showed (2010) al. et Williamson and (2009) al. et Mayhew Indeed, involved. is PI3K/Akt/mTORpathway the of activation that seems it Nevertheless, have phenomenon. this studies in few involved pathways elderly, signaling the the investigated in training aerobic and muscle resistance in increase after an synthesis shown protein have studies many Although 2004). al., et Short 2011; al., et (Konopka synthesis MyHC and synthesis protein muscle mixed increased with associated demonstrated also reserve) rate heart (3 program aerobic intensity moderate- 3-month a completed who subjects elderly strength, in gains profound most the with associated typically is training resistance although Interestingly, 2000). al., et (Hasten only with and results, Moreover, (1RM). repetition and low upper the between alternating exercises multiple of sets three to two with day) rest 3 lasted studies cited the in used programs training resistance Typically, 1993). al., et Yarasheski 1999; al., et Yarasheski 1995; al., et Welle 2000; al., et Hasten 2001; al., et (Balagopal strength muscle and mass muscle of improvement with associated always are increases these exercise, resistance to response prot myofibrillar of synthesis the particular, in 1993), al., et Yarasheski 1999; al., et Yarasheski 1995; al., et Welle 2004; al., protein et Short 2000; muscle al., et Hasten mixed 2001; al., et (Balagopal increase synthesis specifically can exercise that showed 1993) al., studies et Yarasheskinumerous 1995; al., et Welle 2000; al., et (Hasten people older in exercise Issue:Special Aspects Frailty” “Molecular and ofSarcopenia er 6.1.1. is uh s My as such eins oy a gauly nraig nest fo 50 from intensity increasing gradually at body, trophi lhuh hl-oy rti snhss per t b ucagd y resistance by unchanged be to appears synthesis protein whole-body Although Exercise during Exercise proteinaging improves balance ed Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 kltl uce f l rt idctd iia mcaim. ned chronic Indeed, mechanisms. similar indicated rats old of muscle skeletal (aaoa e l, 01 atn t l, 00 Wle ta. 19) In 1995). al., et Welle 2000; al., et Hasten 2001; al., et (Balagopal HC Comment citer cedocument: 2 weeks, the beneficial effect will persist for as long as 3 months months 3 as long as for persist will effect beneficial the weeks, – 5 days per week, with sessions of 20 of sessions with week, per days 5 1 ek f eitne xrie s ufcet o ban these obtain to sufficient is exercise resistance of week – 4 months, with three sessions per week (separated by a by (separated week per sessions three with months, 4

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29 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of MAFb and MuRF1 (i.e., E3 ligase ubiquitin studied widely the of expression the on data available training physical to response in rodents and people older in been measured never has activity proteasome knowledge, our of best the to Moreover, scarce. are sameattheare downregulated time. others recycled be while systems, proteolysis may several of activity the increases exercise synthesis; protein proteolysis during from acids amino proteolysis; measure to used techniques 1993) etal., (HastenYarasheski etal., etal., Welle 1995; 2000; has subjectsno effect onproteolysis of functions the (slow fast)and muscle ofthese or evolutiontypes different responses in over the decades. responses explore to and training of test combinations to and needed types is various research Further training. to response in pathways signaling protein synthesis the explored have that animals old or people older on studies few very are there Finally, 2012). al., 2014;al., Pasini et et Pagano 2008; al., et (Kim muscles hypertrophied with associated activation mTOR and Akt and muscle skeletal in content protein IRS-1 and IGF-1 increases rats old in training) treadmill or exercise wheel running (lifelong exercise aerobic Issue:Special Aspects Frailty” “Molecular and ofSarcopenia animals is related to autophagy regulation. In humans and rodents, sarcopenia is associated is sarcopenia rodents, and humans In regulation. autophagy to related is animals in UPS the on exercise of people. sarcopenic effect the determine definitively to needed are studies more 2010) al., et Williamson 2010; al., et (Konopka MAFbx or MuRF1 of expression the 20 week, per 70 week, per days protein MuRF1 of content muscle in decrease marked a showed (2009) al. et LeBrasseur m/min), 10 at session per min 20 week, per days 5 weeks, (4 training treadmill low-intensity and short same to subjected mice old in the way, In content. protein and mRNA MuRF1 muscle in decrease marked a with along proteinofubiquitinated content muscle in decrease a withassociatedis years) 72 age (mean su decrease evsd nuac tann i ptet wt crnc er fiue n msl atrophy muscle and failure heart chronic with patients in training endurance pervised Ti peoeo my e xlie i svrl ways several in explained be may phenomenon This . x) and muscle ubiquitinated protein (marker of E3 ligase activity) seem consistent with consistent seem activity) ligase E3 of (marker protein ubiquitinated muscle and x) Data on the effects of exercise on the UPS systems in elderly people and old rodents rodents old and people elderly in systems UPS the on exercise of effects the on Data elderly in aerobic) and (resistance exercise that shown have studies various date, To h ms poone efc o eecs o poelss n h edry n older and elderly the in proteolysis on exercise of effect pronounced most The d ciiy f P atr training after UPS of activity Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 – min per session, 60 session, per min 45 – 75% 1RM) or or 1RM) 75% Comment citer cedocument: a moderate-intensity aerobic program (12 weeks, 3 weeks, (12 program aerobic moderate-intensity

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31 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of For 2008). al., et Verney 2009; al., et Verdijk 2010; al., et Shefer 2007; al., et Mackey 2013; al., et (Leenders strength and mass muscle in improvement with along rodents older 2006) on exercise of effect any demonstrate explained be by strength,cleavedthus3resulting caspase production, inof inhibition muscle improve and massand gastrocnemius the in c cytochrome muscle of concentration cytosolic reduced by of accompanied loss the prevent training resistance of weeks 9 that found (2013) al. et Luo Recently, activity. 9 caspase in increase age-related the reverses exercise that showed they addition, a In 2010). to al., access et (Wohlgemuth free wheel withrunning exercise lifelong to subjected rats on same data similar the published Furthermore, group strength. grip forelimb and tolerance exercise in improvements by accompanied were adaptations These fragmentation. DNA apoptotic of levels reduced TNF- of upregulation age-related Indeed,reversed exercise the deathreceptorEDLofoldthe rats. pathwayapoptosis inthe of downregulates training exercise treadmill 4-week that found (2008) al. et Marzetti Similarly, fiber increased cross an by accompanied is apoptosis of severity reduced the that noteworthy rats the in fragmentation DNA apoptotic of gastroc extent the consequence, a As rats. exercising you reaching 2 session) Bcl- of levels Conversely,rats. old of extracts gastrocnemius per in Bax of expression the reduces min 60 week, per days (5 exercise treadmill 12-week that showed (2006) al. on humans. are older no data available 2010) al., et Wohlgemuth 2006; al., et Song 2008; al., et Marzetti 2013; al., et Issue:Special Aspects Frailty” “Molecular and ofSarcopenia are increased in trained rodents, resulting in a dramatic decrease in the Bax- the in decrease dramatic a in resulting rodents, trained in increased are 6.1.3. show the levels of apoptosis similar to those observed in young control animals. It is It animals. control young in observed those to similar apoptosis of levels the show , most of them showed exercise-related activation of the latter in elderly people and people elderly in latter the of activation exercise-related showed them of most , etoa ae aog ih nrae msl wih (oes n gastrocnemius). and (soleus weight muscle increased with along area sectional This topic was reviewed well by Snijders et al. (2009). Although some studies failed to studiesto failed some Although (2009). al. et Snijders by reviewedwell was topic This may fragmentation DNA decreased or myonuclei apoptotic of number decreased The Regarding the effects of exercise training on myonuclear apoptotic signaling, Song et et Song signaling, apoptotic myonuclear on training exercise of effects the Regarding nemius is significantly attenuated by the exercise intervention, such that old trained old that such intervention, exercise the by attenuated significantly is nemius Exercise during Exercise aging stimulates Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 th -related values. In addition, cleavage of caspase caspase of cleavage addition, In values. -related a renewallatter ofthe thanks Comment citer cedocument: R1

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32 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of activity synthase citrate in rate production ATP mitochondrial in increase an years) 4 past the during week per days 6 least(performingat people traineddemonstratedolder in (2008) al. et Lanza Indeed, aging. during function mitochondrial improve and biogenesis mitochondrial 1α, (PGC- muscle skeletal in biogenesis mitochondrial in involved genes of mRNA in and COX4), (e.g., genes mitochondrial of levels mRNA in oxidase), c cytochrome and synthase (citrate increases min) 40 for rate heart maximal of 80% at week per sessions four weeks, (16 training endurance the traini exercise resistance-type of months 6 that showed who (2013), al. et Leenders by confirmed in increase specific a by accompanied was and fibers muscle II type for specific was hypertrophy muscle skeletal observed The men. elderly healthy in strength muscle increase and mass, fat reduce mass, muscle increase 1RM) 80% week, per days (3 training resistance of months 3 that found (2009) al. et Verdijk instance, Issue:Special Aspects Frailty” “Molecular and ofSarcopenia to sit- decreased and extension leg maximum one-repetition of strength increased in resulting of of mitochondrial in increase expression Anthe in and/or proteins, 2003). mitochondrial of expression the al., in number, and et function Short 2004; al., et Short 2010; al., et Safdar 2002; al., et Radak 2002; al., et Malbut 2008; al., et Lanza 2007; al., et Lambertucci 2012; al., et Koltai 2005; al.,et Huang 1992; al., (Hammerenet rodents and adults older in capacity increase significantly can week) per h 1 of sessions 3 with weeks II type of size increased an session): numbers.fiber SC accompaniedincreaseby muscle an in per min 20 week, per days 6 training, treadmill of weeks (14 rats old and training) resistance upper-body and endurance lower-body combined of weeks (13 elderly the in training endurance to response the on results similar reported (2010) al. et Shefer and (2008) al. et Verney hand, other the On content. SC and myonuclear -stand time. These results were accompanied by a type II muscle fiber-specific increase in increase fiber-specific muscle II type a by accompanied were results These time. -stand rncito fcos novd n iohnra boeei ae ehnss ht explain that mechanisms are biogenesis mitochondrial in involved factors transcription NRF- above improvements. Short et al. (2003) were among the first to show in humans that humans in show to first the among were (2003) al. et Short improvements. above 6.1.4. ng (3 days per week, 80% 1RM) lead to increased lean mass mass leanincreased leadto week,1RM)80% per days (3 ng Aerobic exercise of sufficient intensity (at least 60% 60% least (at intensity sufficient of exercise Aerobic 1, and TFAM). These results suggested that aerobic exercise could induce de novo de induce could exercise aerobic that suggested results These TFAM). and Exercise during aging improves mitochondrial function and dynamics during Exercise mitochondrial improves function aging Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006

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33 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of muscle and strength in gains profound most the to leads training resistance here, discussed and effects deleterious the all on act can it because sarcopenia against countermeasure 2014; also are review, this al., et (McGregor mass of muscle controlling microRNAs scope of regulation better as such the involved, beyond are which mechanisms, other but exercise, weeks ho of 9 after concentration muscle mitochondrial skeletal in increased C cytochrome an with associated increased found phosphorylation (2013) al. AMPK et Luo rats, older in Moreover, chain. transport electron the of ofimprovement an increase in activity,complex(2005) IV al. reflectingfound Parise et 1RM), improvement of 80% older week, per with sessions in (three training However, resistance whole-body of topic. associated weeks 12 this after people on not available are usually studies few very is function, mitochondrial training resistance Because CSA. PGC- 1, protein fission 2, and mitofusins of levels protein increased showed people elderly trained Indeed, reserve). rate heart 80% at week per min 45 of sessions (four training aerobic after people older in results of levels numb protein on the in data reduction a reflect may quantitative finding this protease); Lon and to 1, protein fission 1, (according mitofusin rats young in observed those to similar canmitochondrialfission)tolevels restoreand dynamics (fusion aerobicexercise that an by driven is abundance) mtDNA increased and muscle in COX4 and dehydrogenase, succinate PGC- of levels protein increased to (according biogenesis mitochondrial increased that w (6 rats trained old al. in et showed Koltai (2012) recently, More muscle. skeletal in II and I subunits COX of levels protein and activity IV complex increases people older in activity physical that found they Furthermore, and strength isometric maximal in increase (an improvements functional with associated are they that also was 1α) PGC- stimulate to (known 3 Sirt of level protein increased an Moreover, abundance. mtDNA Issue:Special Aspects Frailty” “Molecular and ofSarcopenia wever, physical parameters were parameters wever,not physical measured. t h sm tm, mrv msl ms, tegh ad hscl efrac. As performance. physical and strength, mass, muscle improve time, same the at increase in Sirt 1 activity and AMPK phosphorylation. Moreover, these authors found authors these Moreover, phosphorylation. AMPK and activity 1 Sirt in increase ia e a. 21; apei t l, 2015). al., et Zampieri 2014; al., et Rivas er of impaired mitochondria. Konopka and Sreekumaran Nair (2013) confirmed these confirmed (2013) Nair Sreekumaran and Konopka mitochondria. impaired of er Here, we presented the main molecular mechanisms of prevention of sarcopenia by by sarcopenia of prevention of mechanisms molecular main the presented we Here, Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 observed. a decrease in time to perform the 30-feet walk test and stair climb tests). tests). climb stair and test walk 30-feet the perform to time in decrease Comment citer cedocument:

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34 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of edd o id h te pia rgmn f diitain Crety intermittent Currently, administration. of regimen optimal the the find to needed effects numerous beneficial despite significant that showed study This study. the stop to organizers the causing thus placebo, receiving men to compared as cardiovascular testosterone receiving men more in occurred events adverse Nevertheless, testosterone. free and total serum of upregulation (DXA) bod of 15% to equivalent weight a of also basket a was lowering and fatigue lifting involving Muscle tests by tests. assessed, walk 40-meter and climb stair 12-step a using evaluated Muscle function. physical was function Physical andstrength. press chest and press leg of means by assessed was strength strength muscle improves mobility) with years; in 74 limitation (age men severe community-dwelling in months) 6 for daily gel testosterone of g (10 therapy testosterone whether determine to was trial randomized placebo-controlled conducted trial (TOM) Limitations Mobility with 2013) al. et Maggio 2006; al., et (Ottenbacher performance physical and strength, mass, muscle 5α or testosterone that concluded . trials controlled randomized recent most the reviewed who (2013), al. et Maggio by completed recently was meta-analysis This 2006). al., et (Ottenbacher older and derivative potent more its or (testosterone treatment androgen whether determine to meta-analysis of methods numerous Consequently, 2012). Yamaguchi, and Sakuma sarcopenia hormone replacementhavetoreverse tried researchers using therapies. 2013; al., et Maggio 2012; play age) with decrease combatsarcopenia. to solution best the be to appears separately training endurance and cycles training resistance mass Issue:Special Aspects Frailty” “Molecular and ofSarcopenia 6.2.1. 6.2. y weight. Finally, lean body mass was determined by by determined was mass body lean Finally, weight. y , whereas whereas . Th . . All these parameters were enhanced by this treatment and were associated with associated were and treatment this by enhanced were parameters these All . In 2006, the findings from 11 randomized controlled trials were examined using the using examined were trials controlled randomized 11 from findings the 2006, In and testosterone particular in hormones, that evidence is There

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35 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of (Kovac rodents in sarcopenia reversing at effective is testosterone that shown was it recently, More TNF- of concentration plasma the reduce 2010) al., et (Fernandez-Balsells function and by oxygenation muscle mechanism improves additional hormone this an which considered be can effect with this associated hemoglobin; also of upregulation is treatment Testosterone 2011). (Grossmann, pathway mediated promotes also Testosterone activatio 2012). al., et (Dubois motoneurons) of activity increase and rate, breakdown protein the decrease to acids, amino intracellular of recycling improve to synthesis, protein muscle stimulate to known is new are Yarrow, and treatments, 2015) (Borst testosterone transdermal of effects or adverse decrease oral to tested of being approaches instead injections prostate), on effects 5α with associated treatments and/or treatments Issue:Special Aspects Frailty” “Molecular and ofSarcopenia levels decline progressively after 30 years of age at a rate of ~1% per year. In aged men, aged daily In year. of~1%rate progressivelya decline per ofage levels 30years at after explain and apoptosis and damage levels ( levels 2012) al., et (Giannoulis secretion GH inhibits which somatostatin, and secretion, GH stimulates factors hypothalamic two of actions the by controlled is secretion GH 1988). al., et (Ho meals after hours few a episodes less secretory and conspicuous sleep slow-wave of onset the at surge major a with manner pulsatile a in occurs GHsecretion1996). etal., (Florini including skeletal muscle tissues, of multiple target growth postnatal coordinates GH gland. pituitary anterior the of cells somatotopic the by mainly Moreover, protein. to due (G6PDH) pathway inhibitionand (Kovacheva myostatin 2010).etal., activation Akt signaling Notch the dehydrogenase though activation SC 6-phosphate to led treatment glucose testosterone the of content 6.2.2. Mroe, etseoe em t hv at-nlmaoy fet bcue t can it because effects anti-inflammatory have to seems testosterone Moreover, . . . The secretion of GH is maximal at puberty, accompanied by very high circulating IGF- circulating high very by accompanied puberty, at maximal is GH of secretion The . heva et al., 2010) al., et heva

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36 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of plasma and hepatic in resulting doses with h), 17:00 and 10:00 at injections: subcutaneous pulsat the mimicking treatment a using Similarly, synthesis. protein increased concomitantly the to due likely volume) and weight muscle by (assessed hypertrophy muscle with associated tension tetanic maximal in anincrease observed et 2000) al., (Andersen weeks), during12 day kgper per mg of improvement any find not did researchers other contrast, In 2002). al., et (Lange isoform 2X My the upregulationof substantial to leads GHtherapy shownthat has been itmen, older with common more were arthralgia as such effects adverse some Unfortunately, mass. body lean in changes to related directly was and GH of influence to compared as Furthermore, higher testosterone). was (receiving group which another mass, lean in increase an with along decrease mass fat a showed men Treated week. per times three subcutaneously weight) body µg/(kg 20 receiv who years, 88 to 65 aged men US community-dwelling ambulatory, healthy, al. et Blackman a by on published (2002) were data Similar strength. thigh and mass, muscle mass, body lean increases week) per times three subcutaneously, weight body of kg per mg (0.03 months 3 for treatment GH that found (1996) al. et Welle old, 60years over subjects healthy in instance, For 1996). al., et Welle 2002; al., et Brill 2002; al., et (Blackman GH of months) (3 administration long-term and short- after strength in improvement an demonstrated phys somatostatin in increase an to (Kelijman,1991). secretion and GHRH of downregulation to secondary is secretion GH in decline age-dependent The episode). release a within attained secretion GH of rate (maximal age with amplitude burst secretory GH in decrease a found (1995) al. et Veldhuis Moreover, 2008). al., et (Ryall adults young in that than lower 20-fold to 5- is secretion GH Issue:Special Aspects Frailty” “Molecular and ofSarcopenia erto (aua n Ymgci 21) I aia mdl, eeiil fet wr also were observe effects beneficial models, animal In 2012). Yamaguchi, and (Sakuma secretion GH natural of pattern pulsatile the mimic to treatment GH exogenous of failure example: 2012) uce tegh r uce as after mass muscle or strength muscle cl efrac ae tl dbtd Ganui e a. 21) Sm researchers Some 2012). al., et (Giannoulis debated still are performance ical . ile pattern of natural GH secretion secretion GH natural of patternile h efcs f H diitain n lel pol o msl ms, tegh and strength, mass, muscle on people elderly in administration GH of effects The hr my e eea raos o te ak f fetvns o G tetet for treatment, GH of effectiveness of lack the for reasons several be may There d when recombinant human GH was used. Indeed, in old rats treated with GH (2.7 GH with treated rats old in Indeed, used. was GH human recombinant when d Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 we rnoie, obebid paeocnrle prle-ru til in trial parallel-group placebo-controlled double-blind, randomized, 26-week of calf musculature (soleus, plantaris, gastrocnemius, tibialis anterior, EDL) anterior, tibialis gastrocnemius, plantaris, (soleus, musculature calf Comment citer cedocument:

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40 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of specificHaoand studies2011),2013; etal., al., are needed. et (Alwaycircumstances muscle-deconditioning other with combination in only studied been 2013 al., etBaptista 2013; al., et (Alway immobilization) or (HU models hypodynamia and hypokinesia 2008a, TNF- as such treatments muscle-wasting to response in of models 2014) Callahan, and Supinski 2010; al., Kovariket 2008a; al., experimental et (Eley endotoxemia and sepsis and 2013), 2012; al., et al., Nunes 2015; et al., et (Aversa Giron treatments 2013; al., glucocorticoid et Baptista 2005), al., et Smith 2008; al., et 2014b; al., Nunes et Mirza 2007; al., et Eley 2007; al., et Caperuto 2011; al., et (Aversa cachexia reported been also has lines cell and rodents in conditions muscle-deconditioning various in HMB of Efficiency 2001). al., et Vukovich 2013; al., et Stout 2002; al., et May 2010; al., et Hsieh 2004; al., et Flakoll 2013; al., et Deutz 2009; al., et (Baier (Clark AIDS 2002), al., et (May cachexia cancer example, for performance, physical and strength by characterized conditions deconditioning canlastlonger. wasting conditionsother as such cachexia longe the show and rodents because studied canbe treatments long veryof safety Moreover, 2014). al., in et (Fuller effects only studied been has which FaHMB, of safety the with ha but study human previous any in reported been not co 2014), al., et mg/[ (Yonamine (320 CaHMB with weeks 4 for treated rats healthy young in reported been have intolerance glucose higher and sensitivity insulin in adecrease possible However, 2013). al., et Wilson 2014; al., et (Szczesniak reviewed and studied well been h/day. ~15 for HMB Issue:Special Aspects Frailty” “Molecular and ofSarcopenia mpared to rats treated only with gluco with only treated rats to mpared 6.3.2. t l, 00, hoi osrcie umnr dsae Hih t l, 20 al., et (Hsieh disease pulmonary obstructive chronic 2000), al., et Beneficial effects of HMB in human subjects have been reported been have subjects human in HMB of effects Beneficial b) ; Hao et al., 2011; Mirza et al., 2014b). In animals, effects of HMB during aging have have aging during HMB of effects animals, In 2014b). al., et Mirza 2011; al., et Hao ; st , HMB: a very potent againststrategyconditions avariousvery HMB: muscle-wasting study lasted for 1 year (Baier et al., 2009), whereas treatment of sarcopenia or sarcopenia of treatment whereas 2009), al., et (Baier year 1 for lasted study a Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 os mdl f uhne uclr ytoh (an e a. 20) and 2006), al., et (Payne dystrophy muscular Duchenne of model mouse Ca Comment citer cedocument: HMB is completely safe, and its safety in humans and animals has animals and humans in safety its and safe, completely is HMB or n as rae wt guootcis obnd ih M, as HMB, with combined glucocorticoids with treated rats in

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42 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of proteasom lesser by explained be may HMB completely axisis unknown. IGF-1 in observed were results Similar 2009) al., et (Kornasio 2011). SCs human cultured al., et (Gerlinger-Romero placebo a receiving IGF- higher with along gland, pituitary the higher show GH with treated rats young healthy Indeed, is which kno axis, GH/IGF-1 the of activity increased an by explained be may treatment HMB . 2014a) al., et Kimura b; 2008a, al., et Eley 2007; al., et Eley 2012; al., et (Aversa II angiotensin and TNF- as such treatments muscle-wasting todifferent exposed cells muscle of culture on studies numerous in reported were results Similar 2011). al., et (Aversa phosphorylation p70S6K and mTOR of activation increased with associated is HMB by rats cachexic in loss mass gastrocnemius of prevention Indeed, targets. its and pathway PI3K/Akt/mTOR the of activation by explained be may supplementation HMB after synthesis 2005) al., et Smith 2010; al., et Kovarik 2015; al., et Giron b; 2008a, al., et Eley 2007; al., et Eley 2012; al., et (Aversa models muscle-wasting cellular and animals 200 decrease al., et Flakoll 2013; al., et Deutz 2009; in al., increase et an (Baier synthesis by protein caused muscle be to seems improvement balance Protein 2010). 2004; al., al., et et Flakoll Hsieh 2013; al., et Deutz 2009; al., et (Baier turnover protein improving by physical of deterioration performance functions and dynamics mitochondrial of impairment sarcopenia, while during strength muscle and mass muscle in decrease the explain largely may process regenerative and apoptosis between imbalance an and turnover protein data. negative of lot a provided cultures cell and animals on studies but humans, in well studied been not have performance physical of deterioration Issue:Special Aspects Frailty” “Molecular and ofSarcopenia 6.3.4. n o mrv poen ytei truh TR ciain Shafn e a. 2013) al., et (Schiaffino activation mTOR through synthesis protein improve to wn In elderly subjects, HMB increases muscle mass or prevents a muscle mass decrease mass muscle a prevents or mass muscle increases HMB subjects, elderly In prevents HMB which by Mechanisms Decreased protein breakdown observed in the elderly receiving a supplement supplement a receiving elderly the in observed breakdown protein Decreased The stronger activationstrongerThe the of PI3K/Akt/mTOR its in responsepathway targets and to in Molecular and cellular mechanisms by which HMB prevents muscle wastingmuscle Molecular andwhichby cellular mechanisms HMBprevents protein breakdown (Hsieh et al., 2010). Similar data have been published about published been have data Similar 2010). al., et (Hsieh breakdown protein Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument:

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43 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of This group. placebo a to compared as HMB, with treated rats old hindlimb-unloaded of plantaris decrease dramatic a by judging apoptosis, decrease can HMB elderly.Indeed, the in mass muscle effecton protective HMB’s muscle-wasting andconditions. moregenerallyunder sarcopenic Akt under HMB of via effects the explore to and needed are data More 2015). phosphorylated-FoxO3/total-FoxO3 al., et (Giron activation ratio increased the through pathway autophagy the musclenormalizesdexamethasone-inducedof cells However,HMBtreatment 2013) al. et Kim 2013; al. et Fry 2013; al. et O’Leary 2010; al. et Wohlgemuth 2009; al. et autophagy although (McMullen sarcopenia available; during decreases it 2015), al., et are (Giron GCs to response in treatments increases glucocorticoid to response in obtained supplement a receiving subjects aged in observed balance confirmed. et al., be mechanisms (Schiaffino Nonetheless, these 2013). need to et (Aversa TNF- of expression decreased by mediated 2006) al., et Hsieh 2008b; al., et (Eley effects antioxidant and anti-inflammatory its to due be could HMB by ligases ubiquitin E3 and proteasome of Inhibition 2014a). al., et Kimura 2015; wasting to TNF- as such treatments exposed cultures cell muscle in obtained been have data Similar rats. control to compared as expression MuRF1 muscle reduces months) (20 rats male aged sedentary group placebo a to compared as HMB, Similarly, receiving and GCs with the treated in rats content of protein MyHC soleus total higher and MyHC ubiquitinated less with associated these with line In mice. result control cachexic to compared as muscles, hindlimb in subunits showed (2005) al. proteasom et decreased Smith HMB, receiving mice cachexic in Indeed, wasting). muscle in involved ligases ubiquitin E3 important (two MuRF1 and MAFbx of expression lesser with Issue:Special Aspects Frailty” “Molecular and ofSarcopenia effect of HMB was due to downregulation of cleaved caspases 3 and 9 in the soleus and soleus the in 9 and 3 caspases cleaved of downregulation to due was HMB of effect s , The decrease in apoptosis in response to HMB supplementation may be involved in involved be may supplementation HMB to response in apoptosis in decrease The HMB Noh et al. (2014) found decrease found (2014) al. et Noh Russ et al. (2015) showed recently that HMB treatment thatHMBrecently showed (2015) al.et Russ al., 2012; Townsend et al., 2013), which are known to activate the UPS system UPS the activate to known are which 2013), al., et Townsend 2012; al., ’s Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 fet n uohg my e novd n h ipoeet f h protein the of improvement the in involved be may autophagy on effect al Comment citer cedocument: ciiy ln wt a erae n rti cnet f proteasome of content protein in decrease a with along activity α , IFN- ,  , and GCs (dexamethasone) (Aversa et al., 2012; Giron et al., et Giron 2012; al., et (Aversa (dexamethasone) GCs and in h nme o TNLpstv nce i te oes and soleus the in nuclei TUNEL-positive of number the

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44 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of confirmed. has to be this eventually thus activity synthaseresult citrate increased to leading activation, AMPK through 2013) Zemel, and (Bruckbauer myotubes C2C12 in resveratrol with synergistically AMPK activate 2014) al., et (Liang myotubes C2C12 in consumption muscle NRF-1 hindlimb genes electrostimulated biogenesis mitochondrial stimulates in leucine that demonstrated velocities relaxation as well spec raises and rats healthy young of muscle skeletal the in activity synthase citrate and content glycogen and ATP increases supplementation HMB that found (2012) al. et Pinheiro Indeed, fusion/fission). and biogenesis (mitochondrial dynamics and functions mitochondrial better inHMB-treatedal.,(Alway muscles 2013). et apoptosis muscles sarcopenic in changes functional and muscle in changes hypertrophic support to potential transcriptional the promote should Enhanced A cyclin and 2 differentiation of markers proliferation of levels protein nuclear the increased HMB Furthermore, animals. vehicle-treated from muscles reloaded to compared as muscles plantaris reloaded HMB- in myonuclei, all to relative myonuclei MyoD/myogenin-positive of number greater byjudging stemcellsnumberofdifferentiatedgreater awas there result,a As 2013). al., et SC P and PAX7- bromodeoxyuridine-positive, of numbers du on acting 2009)al., et (Kornasio cultures cell muscle in obtained were data Similar 2011). al., et (Hao plantaris Issue:Special Aspects Frailty” “Molecular and ofSarcopenia proliferative state) in the plantaris of HMB-treated rats compared to control rats (Alway rats control to compared rats HMB-treated of plantaris the in state) proliferative ring muscle recovery after hindlimb unloading. Indeed, th Indeed, unloading. hindlimb after recovery muscle ring ific force generation and resistance to acute fatigue (without changes in contraction) as contraction) in changes (without fatigue acute to resistance and generation force ific ing in better physical performance in HMB-treated elderly people elderly HMB-treated in performance physical better in ing Cneunl, t a b hpteie ta HB ciae mtcodil biogenesis mitochondrial activates HMB that hypothesized be can it Consequently, . hog AP atvto ad nrae mtcodil as b 3% ad oxygen and 30%) (by mass mitochondrial increases and activation AMPK through ial, M my atcpt i peeto o msl ms ls i te lel by elderly the in loss mass muscle of prevention in participate may HMB Finally, Increased physical performance in aged subjects treated with HMB may also involve also may HMB with treated subjects aged in performance physical Increased . SC

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46 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of need not does Catalase 1993). al.,et (Scott NADPH on depends which reductase, glutathione by glutathione reduced of production the on dependent system glutathione the is first The activated in summarized are and G6PDH 1989) regulate also al., factors et (Barakat muscle skeletal rat in activity muscle G6PDH increase to with found also associated content was training protein Aerobic 1984). Max, 2010; al., et and Kovacheva 2014; al., et (Brioche PI3K/Akt/mTOR hypertrophy activity the G6PDH activate increase to can (known treatments pathway) GH and testosterone that shown been has it rodents, old of muscle skeletal the In effectors. downstream their and factors NADPH NADPH impor extensively cells mammalian in enzymes princ the as described originally were which (GDH), dehydrogenase glutamate and (ME), enzyme skelet productionenhancing their G6PDHby exp be will it paragraphs, following the In (PGD). dehydrogenase 6-phosphogluconate pathway, the Issue:Special Aspects Frailty” “Molecular and ofSarcopenia below molecules intracellularmany of target downstream the is G6PDH location. the by and levels post-translational and translational, transcriptional, the at regulated tightly is G6PDH vivo. in not but 1976) al., et (Holten vitro in demonstrated clearly to lead that 1994) al., et (Kletzien oxidants extracellular various to cells of exposure after activated is G6PDH Indeed, NADPH. more provide to increases activity decreases, ratio the as that so I cytosol. pl ore o NDH n iohnra Tu, AP i mil poue b five by produced mainly is NADPH Thus, mitochondria. in NADPH of sources ipal l uce el ad rvds AP a d ioirt dhdoeae ID) malic (ICDH), dehydrogenase isocitrate do as NADPH provides and cells muscle al tance to many cellular processes that use NADPH because inhibition of G6PDH lowers G6PDH of inhibition because NADPH use that processes cellular many to tance . and h va AP ad 5, 6D my e novd n acpna n why and sarcopenia in involved be may G6PDH R5P, and NADPH via why lained Several antioxidant systems depend on the production of NADPH for proper function. function. proper forofNADPH production onthe dependsystems antioxidant Several It has been traditionally thought that G6PDH is regulated by the NADPH/NADP ratio NADPH/NADP the by regulated is G6PDH that thought traditionally been has It the in NADPH of source principal the as only described was G6PDH ago, long Not (Hecker 2012)etal., Stanton, 2013; a ees hc r o ananda omllvl yteohrezms producing enzymes other the by levels normal at maintained not are which levels, by growth factors; this finding is suggestive of a role in cell growth, as discussed as growth, cell in role a of suggestive is finding this factors; growth by t decrease in the level of NADPH. Regulation by the NADPH/NADP ratio has been has ratio NADPH/NADP the by Regulation NADPH. of level the in decrease n pa cuil ellr oe. 6D, oee, per t b o unique of be to appears however, G6PDH, roles. cellular crucial play and was Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 eety hw, oee, ht 6D i peet n h mtcodi of mitochondria the in present is G6PDH that however, shown, recently Comment citer cedocument: : 6D, -G, CH M, n GH Al ae en studied been have All GDH. and ME, ICDH, 6-PGD, G6PDH,

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47 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of Salvemini 2005; al., et Nutt 2004; al., et (Fico apoptosis and content protein and/or activity al., et (Leopold cells 2003) wild-type to compared as production species reactive nitrogen decreased and in oxygen results cells endothelial in overexpression G6PDH Similarly, mice. sarcopenic in content protein G6PDH in decrease dramatic a detected (2008) al. et Braga Moreover 1975). al., et (Askeq muscle skeletal and liver the in activity G6PDH increase can to response in exercise aerobic micethat shown been has old it animals, young In precursor. regarding GSH a with treatment (2013) al. et Sinha-Hikim by published were results and activation Akt incre to able is mice old of treatment testosterone Indeed, topic. this on data published (2010) the mu and synthesis you protein reestablish restoring to by important very sarcopenia is which combat status, redox to associated strategy good a be would G6PDH targeting 2010; was activities SOD and Cat, Gpx, GR, observe GSH, in increase concomitant a muscle; skeletal in increased is activity or content protein G6PDH rats, of treatment GH or testosterone or strategies antioxidant different to response in hand, other the On 2013). al., et Sinha-Hikim 2004; al., et Kumaran 2010; al., et Kovacheva 2014; al., et (Brioche oxidation protein and DNA and peroxidation lipid in increase concomitant observed the explain may observations 2014; al., et (Brioche SOD and of catalase, (Gpx), contentperoxidase glutathione (GR), protein reductase glutathione or activity decreased with associated ratio GSSG/GSH an the GSH, in of increase depletion with associated are content protein muscle and/or activity G6PDH 2012) (Stanton, activity SOD the this inhibit and increase quantitatively if will levels peroxide however, hydrogen peroxide; increased the hydrogen glutathione, or catalase to by chemically reduced superoxide adequately not is convert compound to NADPH use not does dismutase Superoxide 1993). al., et (Scott conformation active its in catalase keep can that NADPH for site binding allosteric an has but water to peroxide hydrogen convert to NADPH Issue:Special Aspects Frailty” “Molecular and ofSarcopenia scle regenerative potential (Derbre et al., 2014). As mentioned above, Kovacheva et al. et Kovacheva above, mentioned As 2014). al., et (Derbre potential regenerative scle ase G6PDH muscle content associated with decreased lipid peroxidation and increased and peroxidation lipid decreased with associated content muscle G6PDH ase oahv e a. 21; uaa e a. 20; ih-ii e a. 21) These 2013). al., et Sinha-Hikim 2004; al., et Kumaran 2010; al., et Kovacheva . .

Kumaran et al., 2004; Sinha-Hikim et al., 2013). These results provided evidence that evidence provided results These 2013). al., et Sinha-Hikim 2004; al., et Kumaran Various studies in cell culture have shown a direct negative relation between G6PDH between relation negative direct a shown have culture cell in studies Various t a be son n aiu suis ht uig acpna n aig decreased aging, and sarcopenia during that studies various in shown been has It d, leading to alleviation of oxidative damage (Brioche et al., 2014; Kovacheva et al., et Kovacheva 2014; al., et (Brioche damage oxidative of alleviation to leading d, Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 SC activation. Eventually, these mice develop muscle hypertrophy. Similar hypertrophy. muscle develop mice these Eventually, activation. Comment citer cedocument:

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48 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of 1998) al., et (Tian content H of effects growth-inhibitory the to susceptible more cells makes G6PDH of inhibition Furthermore, 2000). al., et (Ho rate al., et synthesis protein and DNA increases lines cell various in G6PDH of overexpression that synt essential an R5P, synthetizing comp pathway main the is which pathway, phosphate pentose major with 1978) al., et (Wagner a synthesis RNA and synthesis protein while 1978), al., et Wagner 1977; regenera old various in Indeed, synthesis. protein and RNA, on SCs, of proliferation possible on acting by etal., Sinha-Hikim 2010; 2013) both are protein G6PDH and dow activation Akt muscle, old in studies, aforementioned the Ind Hikim al et (Brioche hypertrophy muscle with and apoptosis associatedis with decreasedcontent protein or sarcopenia,G6PDHactivity increased against strategies different to response in hand, other the On muscle. skeletal in 9 and 2 caspases co al., et Sinha-Hikim 2010; al., et Kovacheva 2008; al., et (Braga atrophy and apoptosis increased with associated is muscle skeletal in G6PDH promotes and (200 al. et Nutt hand, other the On show 2004). al. et (Fico levels protein 9 and 3 caspase high and depletion GSH with a associated apoptosis cells peroxide-induced hydrogen stem to embryonic sensitive G6PDH-null instance, For 1999). al., et Tian 1999; al., et Issue:Special Aspects Frailty” “Molecular and ofSarcopenia fre i od ie ht elto o GPH rti i ascae wt upregulation with associated is protein G6PDH of depletion that mice old in nfirmed eed, Akt is also known to have antiapoptotic effects (Robey and Hay, 2006). Moreover, inMoreover, 2006). Hay, and (Robey effects antiapoptotic have to known also is Akt eed, studies on the muscle degeneration-regeneration cycle, it has been shown that during that shown been has it cycle, degeneration-regeneration muscle the on studies hesis. These various hypotheses were confirmed in in vitro studies, which have shown have which studies, vitro in in confirmed were hypotheses various These hesis. nregulated and associated with muscle atrophy (Brioche et al., 2014; Kovacheva et al. et Kovacheva 2014; al., et (Brioche atrophy muscle with associated and nregulated G6PDH inhibition (Wagner et al., 1978). Thus, it was argued that G6PDH may perform a perform may G6PDH that argued was it Thus, 1978). al., et (Wagner inhibition G6PDH ed onent of nucleic acids nucleic of onent 1998; Kuo et al., 2000). On the other hand, G6PDH-deficient cells show a lower growthlower show a cells G6PDH-deficient otherhand,the On 2000). al., Kuoet 1998; ucin n RA n DA ytei bcue t s h rt-iiig nye f the of enzyme rate-limiting the is it because synthesis DNA and mRNA in function et al., al., et G6PDH activity may play an important role in muscle hypertrophy and regeneration and hypertrophy muscle in role important an play may activity G6PDH that inhibition of G6PDH by didehydroepiandrosterone (DHEA) activates caspase 2 caspase activates (DHEA) didehydroepiandrosterone by G6PDH of inhibition that tion (known to involve(known to tion 2013) Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 oo cyte apoptosis. In old rodents, decreased activity and/or protein content content protein and/or activity decreased rodents, old In apoptosis. cyte . This beneficial effect may be mediated by a link between Akt and G6PDH.and Akt between link a mayby mediated be effect beneficial . This . Furthermore, inhibition of mRNA and protein synthesis is associated associated is synthesis protein and mRNA of inhibition Furthermore, Comment citer cedocument: . Inhibition of G6PDH in cultured cells decreases their proliferation their decreases cells cultured in G6PDH of Inhibition . Because of this function, G6PDH may indirectly affect protein affect indirectly may G6PDH function, this of Because 2 . O

SC 2 owing to NADPH downregulation leading to decreasedGSH to leading downregulation NADPH to owing s)

, G6PDH activity is dramatically increased (Wagner et al.,(Wagneret dramaticallyincreased isG6PDHactivity 2013) ., 2014; Kovacheva et al., 2010; Sinha- 2010; al., et Kovacheva 2014; . Moreover, Braga et al. (2008) (2008) al. et Braga Moreover, .

re also also increased re more

(Tian 49 of of 5) , Page

49 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of r n are Theresynthesis. protein decreasing thereby PI3K/Akt/mTORpathway, impairthe can change aging during only al., et 2013) al., Sinha-Hikim Kovacheva 2010; now, Until support have synthesis. atrophy and protein decreased activity G6PDH decreased with associated p70S6K to of activation and Akt of downregulation contribute should aging downregulation G6PDH 2010). during al., et Kovacheva 2014; al., et (Brioche damage oxidative with along protein G6PDH show GH of or content testosterone muscle with increased treated rats or mice Conversely, mice. sarcopenic old in damage oxidative in increase an and impaired protein G6PDH of content showed skeletal-muscle in decrease who (2014), al. et Brioche and (2010) activity G6PDH increased hand, sh other the On muscle. skeletal of capacity regenerative th to belongs Animal(RAM) asFacilitiesMontpellier wellas Montpellier RIONetwork the (MRI). Imaging which facility, platform METAMUS our and staff animal-facility the thank to grateful studies Our in 3 Figure summarized are mechanisms these All effects. adverse these reverse and status redox limiting by muscle skeletal of potential regenerative the reduce may activity G6PDH in decrease A caspases. of activation through apoptosis to lead activity G6PDH in the and phosphorylation hand, Akt other in decrease the parallel On 2014). al., et (Derbre pathways proteolysis several of activation and accumulation own their promote should species nitrogen and oxygen reactive defense, protein and (activity downregulation G6PDH that content) hypothesized be can it status redox Therefore, impaired with associated synthesis DNA and protein decreased of because Issue:Special Aspects Frailty” “Molecular and ofSarcopenia ould improve this mechanism. Data in this regard have been published by Kovacheva et al.et Kovacheva by published been have regard this in Data mechanism. this improve ould 7. pbihd aa n 6D ad proteolysis and G6PDH on data published o

Finally, decreased G6PDH activity and/or protein content in skeletal muscle observed muscle skeletal in content protein and/or activity G6PDH decreased Finally, Acknowledgments . —

bevd n kltl uce uig aging during muscle skeletal in observed the Réseau d’Histologie Expérimentale de Montpellier (RHEM) platform. We also We platform. (RHEM) Montpellier de Expérimentale d’Histologie Réseau the are supported by the Centre National d’Etudes Spatiales (CNES). The authors The (CNES).Spatiales d’Etudes NationalCentre the supportedby are Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 may e novd n acpna y eraig h atoiat aaiy this capacity; antioxidant the decreasing by sarcopenia in involved be Comment citer cedocument: ed SC hs yohss n kltl uce Bice t l, 2014; al., et (Brioche muscle skeletal in hypothesis this proliferation. Activated G6PDH Activated proliferation.

.

— ; may oee, y eraig antioxidant decreasing by however, otiue o dces i the in decrease a to contribute SC

SC rlfrto ad decreased and proliferation rlfrto aog with along proliferation sh ould restore the optimal optimal the restore ould are 50 e a . Page

50 of 84

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80 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of by modulated is factor-beta- and microtubule dynamic Research stability. 94,617-625. Circulation pathway growth Smad through Transforming mediated is 2004. myogenesis of C., inhibition induced Dong, P.J., adipose- Goldschmidt-Clermont, human S., of Zhu, differentiation and expansion vitro in derived adipocytes. into 9, 11. stemBMC cells Biol Cell on inhibitors GSK3 of Effects and sciences Biological Zara A, Series gerontology. of medical 163-173. sciences 70(2), age-associated journals delays The exercise decline. physical Lifelong muscle 2015. M., skeletal H., Sandri, A., Kern, Musaro, U., S., Carraro, Boncompagni, F., V., Protasi, Romanello, M., Rossi, De L., Barberi, K., Rossini, N., Sarabon, W., Mayr, V., Tirpakova, M., Sedliak, Cvecka,J., M., Grim-Stieger, A., Pond, S., Burggraf, M., Vogelauer, H., Fruhmann, beta S., Loefler, L., Pietrangelo, S., Zampieri, hydroxy Beta young old and Physiol 5(2), 145-154. men.Clin of 2014. muscles quadriceps the of strength and size The 1985. M., Crowe, M., Stokes, A., Young, M.T., sedentary Nunes, healthy in rats.Wistar Acta physiologica 212(1), 62-74. sensitivity U.F., insulin peripheral impairs Machado, supplementation methylbutyrate L., Guimaraes-Ferreira, Yonamine physiologyE210-214. 265 (21), Pt of journal American The women. and men elderly and young in rate synthesis protein muscle frail in Yarash rate synthesis protein muscle mixed yr 1),E118-125. Pt old.Thewomen (1 andAmericanofphysiology men>/=76 journal 277 increases training exercise Resistance D.R., 1999. Sinacore, M.B., Brown, K.A., Obert, D.L., Hasten, A J., Pak-Loduca, adults: K.E., Yarasheski, older in loss muscle systematic Geriatrand meta-analysis. 168-175. review 61(2), ArchGerontol on supplementation beta-hydroxy-beta-methylbutyrate of Chronic 2011. Wu, V., Wright, B., Goodpaster, M.A., exercisemuscle 172-178. massinmastersPhys preserves athletes. 39(3), Sportsmed lean Smiley, F., Amati, A.P., life-long Wroblewski, and restriction calorie of effects exercise. Experimentalgerontology(2), 138-148. 45 aging: during apoptosis Skeletal and 2010. C., autophagy Leeuwenburgh, muscle H.A., Lees, E., Marzetti, A.Y., Seo, S.E., Wohlgemuth, Issue:Special Aspects Frailty” “Molecular and ofSarcopenia oi LE, diknk, . Fnan, . Vlaei, . Prli P, ai C, 2008. C., Dani, P., Peraldi, P., Villageois, C., Fontaine, B., Wdziekonski, L.E., gosi, H., Xia, Y., Jiang, J., Du, H., Guo, X., Liu, X., Li, C., Huang, G., Niu, K., 2015. Effect 2015. K., Niu, G., Huang, C., Li, X., Liu, X., Guo, H., Du, J., Jiang, Y., Xia, H., eski, K.E., Zachwieja, J.J., Bier, D.M., 1993. Acute effects of resistance exercise on on exercise resistance of effects Acute 1993. D.M., Bier, J.J., Zachwieja, K.E., eski, , C.Y., Teixeira, S.S., Campello, R.S., Gerlinger-Romero, F., Rodrigues, C.F., Jr., Jr., C.F., Rodrigues, F., Gerlinger-Romero, R.S., Campello, S.S., Teixeira, C.Y., , Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument:

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81 of 84 Version postprint Brioche, T.(Auteurde correspondance), Pagano,A., Py,G.,Chopard, A.(2016). Musclewasting and aging: Experimental models,fatty infiltrations,and prevention. MolecularAspects of mechanisms these All may tosarcopenia. lead and synthesis. protein decreasing thus synthesis, mRNA and DNA impair may 5-phosphate ribose apoptosis exacerbate may of downregulation event The synthesis. protein thisand regeneration muscle impede and and proteolysis status, redox the impair should levels NADPH in decrease The 5-phosphate. ribose and NADPH of synthesis active less change to lead may this muscle; skeletal in content protein and/or activity G6PDH in decrease a with sarcopenia. in involved possibly mechanisms G6PDH-linked 3. Figure anteriortibialis(labeling ananti- with the into glycerol of injection intramuscular after days 21 section, intramuscular muscle paraffin-embedded after muscle. anterior days tibialis murine the 21 into glycerol of hematoxylin-eosin-saffron, injection with stained section, muscle (A) of mice. model in glycerol regeneration the skeletal-muscle in induced accumulation IMAT of analysis Histological 2. Figure ankle rightand to unload the foot. foot the around running strap shoulder the and sole thick a with shoe left a with suspension, a with rodents. hindlimb-unloaded and denervated, mice, transgenic including aging and wasting muscle wasting. muscle of induction with experiments line (MDS). System Drawer Mice the including (ISS) Station Space International orbital actual the and rocket, Soyuz a on launched satellite BION sciences life the devices: wasting muscle skeletal study to used models Experimental 1. Figure Issue:Special Aspects Frailty” “Molecular and ofSarcopenia  ° eddw tl psto, r imrin ad mdl f nltrl lower-limb unilateral of model a and immersion, dry position, tilt head-down 6° (D) Human experimental protocols for studies on muscle deconditioning: bed rest bed deconditioning: muscle on studies for protocols experimental Human Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006 Comment citer cedocument:

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Medicine (50), 32p. DOI: 10.1016/j.mam.2016.04.006

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