Reactive oxygen species enhance mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle of senescence accelerated prone mice SAMP8 Valentin Barquissau, Frédéric Capel, Dominique Dardevet, Christine Feillet Coudray, Anne Gallinier, Marie-Agnès Chauvin, Jennifer Rieusset, Béatrice Morio
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Valentin Barquissau, Frédéric Capel, Dominique Dardevet, Christine Feillet Coudray, Anne Gallinier, et al.. Reactive oxygen species enhance mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle of senescence accelerated prone mice SAMP8. Free Radical Biology and Medicine, Elsevier, 2017, 113, pp.267-279. 10.1016/j.freeradbiomed.2017.10.012. hal-01658864
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Distributed under a Creative Commons Attribution| 4.0 International License Version postprint mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : C A R R T R D P B G D V m s f R A c P r t p T h a f R C h u e u k o c t u I l a o h é i e e e e i h c a O a e t i v n e n I e c t u u e b p l c a i v c f a c l r r
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Version postprint VCO 8 prone mice accelerated 1B; phosphatase beta; and alpha receptor activated beta; and 1alpha coactivator PGC significant; not NS, 2; and kappa factor nuclear 8; and 6 subunit subcomplex beta 1 [ubiquinone] dehydrogenase NADH NDUFB8, and NDUFB6 acetylcysteine; 1; protein associated kinase protein activated ribosyl 4; type longus; element response cAMP CREB, IV; subunit Q10; and Q9 coenzyme coQ10; and CoQ9 5’ adenosine ADP, unit; arbitrary A.U., A bbreviations mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance 2 Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : , carbonproduction; VO dioxide - rnfrs; K, ula factor nuclear IKK, transferase; G/M, Glutamate and Malate; G/M/S, Glutamate, Malate and Succinate; GLUT4, Glucose transpor and Glucose Succinate;GLUT4, Glutamate, Malate and G/M/S, Glutamate Malate; G/M, p1 guahoe eoiae 1; peroxidase glutathione Gpx1, :
D nt determined; not ND, RCR, respiratory control ratio; ROS, reactive oxygen species; SAMP8, SAMP8, species; oxygen reactive ROS, ratio; control respiratory RCR, - lig ht - SAMR1, ; chain 10.1016/j.freeradbiomed.2017.10.012 PP2A, protein phosphatase 2; phosphatase protein PP2A,
Comment citer cedocument: - enhancer of activated B cells; NRF1 and NRF2, nuclear respiratory factor 1 factor respiratory nuclear NRF2, and NRF1 cells; B activated of enhancer - apa n bt, eoioe proliferator peroxisome beta, and 1alpha se TN popaae n tni hmlg PPB protein PTP1B, homolog; tensin and phosphatase PTEN, 2 D ad D, NADH ND6, and ND1 , oxygen consumption. nescence accelerated mice resistant 1 resistant mice accelerated nescence - - kappa B; JNK, JNK, B; kappa diphosphate; S, oa guahoe HR, hypoxanthine HPRT, glutathione; total GSH,
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Version postprint preserving activity) IV and II complexes enhanced with associated were produ NADH between imbalance resulting the to regards with adaptations, conflicting These to associated differences these N of months 6 of activity maximal contrast, m higher with agreement in IV, and II complexes of substrates with rates respiration higher and uncoupling evidenced respiration as well 70% m signaling resistant system antioxidant production, SAM to compared stress oxidative enhanced by characterized these associated been reactive Whereas Abstract sl otn n abnltdpoen ws two was proteins carbonylated in content uscle mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance (p<0.05) Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : three
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Version postprint Key words: mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI :
glucose metabolic flexibility, homeostasis, 10.1016/j.freeradbiomed.2017.10.012 Comment citer cedocument:
mitochondrial bioenergetics , oxidative stress , oxidative
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Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : eas o ehne xnhn oiae acti oxidase xanthine enhanced of because
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Version postprint 2 of µl 400 in solubilized were preparation mitochondrial homogenized to the methodof Griffith Marklund method the to according performed were SOD), and (SOD dismutases superoxide manganese and total and catalase (GPX), peroxidase glutathione of (Irka basic T25 Turrax Ultra an using described below instructions. manufacturer’s the following DNP to derivatized were chains side protein the in groups carbonyl The aorta. abdominal quickly separatedfromand removed, connective andfor fat tissues processed furth the from redrawing blood full by euthanized and pentobarbital ani fast, overnight an After Analyse immunosorbent assay( USA). (Waltham, Corporation Electron Thermo from Waltham Electron, Thermo 20, (Konelab analyser automated glucose of concentration Blood Plasma analyses measurement pe expenditure measurement a and min 5 of purge sample a l/min, 0.6 from on was light the and thermoneutrality mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI :
ape wr cletd in collected were samples uce n Mitochond and Muscle enzymes antioxidant of activity Maximal P s o rotein carbonylation rotein (29) n
muscle homogenates (
period. 26 in 100 µl of 2 of µl in 100 , respectively. , )
to quantify and
ALPCO diagnostics, Salem, USA). diagnostics,ALPCO Salem, eprtr qoin (Q rto f VCO of ratio (RQ; quotient respiratory (30) non , 10.1016/j.freeradbiomed.2017.10.012 -
DNP radicalsDNP propanol by Thurax dissecation. 100 µl of muscle homogenate or 100 µl ofpure 100 µl homogenateor muscle of 100µl dissecation. Thurax by propanol
mals . Total glutathione (GSH) level (GSH) glutathione Total :
Comment citer cedocument: - The Oxyblot Oxidized Protein Detection Kit was purchased from Chemicon. from purchased was Kit Detection Protein Oxidized Oxyblot The seiid at ais gyeo ad triglycerides and glycerol acids, fatty esterified rial rial
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Version postprint pellets Analysis ofmuscle mitochondrial using and dilutions serial order and cDNA native all of mixture Hypoxanthine a from made curve standard a using Rotor Rotor the using (qPCR) reaction chain polymerase quantitative reverse was RNA total O respectively. gel agarose on electrophoresis nm 260 at measurement absorbance by determined transcriptase instructions manufacturer's the to transcription ( proteinoxidase was finally onmuscle assessed homogenat H an against calibrated and simultaneously monitored are sample given FLX oxidase, SAFAS xanthine (spectrofluorimete peroxidase horseradish and of presence oxidase the in NADPH Red Amplex for probe the substrates using respectively, the (1mM), xanthine or mM) (100 NADPH xant and oxidaseNADPH of inhibitors the (90µM), allopurinol or μM) (1 DPI of absence or presence the in min 30 for 37°C at incubated were buffer production: peroxide hydrogen oxidase xanthine and oxidase NADPH (Abcam plc (NAD oxidized wer ofdetection simultaneous supernat nirgn Lf Tcnlge, Saint Technologies, Life Invitrogen, e expressed ase nmol/g oftissue. mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance ed from Sequencesed Sigma. are Primer availableuponrequest. - Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI :
Real NAD and NADH NADt, ee sse (ign Courtaboeuf (Qiagen, system Q Gene n wr ijce i te ytm reverse system the in injected were ant , Cambridge, UK). , Cambridge, - - ie uniaie RT quantitative time polymerase chain reaction (RT reaction chain polymerase - - EIS Mnc) Bak el ae sd o mauig akrud n al ecin fr a for reactions all and background measuring for used are cells Blank Monaco). XENIUS, guanine phosphoribosyltransferase (Hprt) as housekeeping gene. Specific PCR primers were primers PCR Specific gene. housekeeping as (Hprt) phosphoribosyltransferase guanine + frs wr asyd n rzn muscle frozen on assayed were forms, ) - transcribed using SuperScript III reverse transcriptase (Invitrogen) before real time time real before (Invitrogen) transcriptase reverse III SuperScript using transcribed reduced and oxidized forms of forms oxidized andreduced 10.1016/j.freeradbiomed.2017.10.012
Comment citer cedocument: +
content assay: content - The redox state form]. redox wasThe expressed as form]/[oxidized [reduced C analysis PCR -
Aubin, France). Levels of mRNA were assessed by reverse reverse by assessed were mRNA of Levels France). Aubin, hine oxidase, respectively. H respectively.oxidase, hine
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es blotting. bywestern homogenates . RNA sample's concentration and integrity were integrity and concentration sample's RNA . Q9 and Q9 - Gene SYBR Green PCR master mix on a on mix master PCR Green SYBR Gene
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Version postprint was performed o #MS130). (MitoSciences Kit Assay Dipstick Activity Enzyme I Complex Morio by described as pellets, spect assessed was activities (COX) oxidase c cytochrome state 3by 4. state ad after assayed measured respectively) 75µM, and 0.5mM 2.5mM, (1.5µM, A/Ascorbate/TMPD/DNP 2.5mM), consumption (Oxyth system against an H sample given a for reactions all and background measuring 5m and 2.5 (5, succinate and malate substrates with 37°C at min 30 for incubated were FLX SAFAS (spectrofluorimeter peroxidase horseradish of presence the in Red Amplex probe the using assessed were isol MgCl (CaK solution preservation a in 4°C animals fasted overnight from mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance - XENIUS, Monaco) XENIUS, 2 Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI :
iohnra ezm activities enzyme Mitochondrial respiration Mitochondrial M mitochondria until mM) 19 phosphocreatine mM; 2.5 ATP mM; 20 taurine mM; 53.3 MES mM; 9.5 preparation mitochondria isolated Muscle ated itochondrial hydrogen peroxide production peroxide hydrogen itochondrial in the presence of respiratory substrates substrates respiratory of presence the in succinate 2
O as described inCapelas described a asyd n .5gm o mtcodil rtis sn glu using proteins mitochondrial of 0.25mg/mL on assayed was 2 erm, Hansatech Instruments, UK) as described by Capel Capel by described as UK) Instruments, Hansatech erm,
di calibration curve. n muscle homogenates from C57B/6J male mice homogenates C57B/6J inthe presencen muscle from notof or
tion of 60µM of atractyloside of 60µM of tion n rote and
as described by Batandier et al. et Batandier by described as 10.1016/j.freeradbiomed.2017.10.012 Comment citer cedocument: (n=10 per group) per (n=10 none (5mM and 5µM), 5µM), and (5mM none t al. et
: Mitochondria respiration rates were measured at 25°C using an oxyg anusing 25°C at measured wererates respiration Mitochondria :
et al 2 EGTA 1.9 mM; K mM; 1.9 EGTA
) wt o wtot oeoe (5 rotenone without or with M), . ( ( 34 Maximal : 32
). ).
ope I ciiy was activity I Complex . Respiratory control rat control Respiratory . euthanized as described above. above. described as euthanized : after the addition of 360µM of ADP ( ADP of 360µM of addition the after
Gastrocnemius glutamate and malate (5 and 2.5 and (5 malate and glutamate ac : The production of mitochondria of production The : 2 iiy f irt snhs (S, ope II complex (CS), synthase citrate of tivity EGTA 8.1 mM; imidazole 20 mM, DTT 0.5 mM; 0.5 DTT mM, 20 imidazole mM; 8.1 EGTA (33) glycerol were . rophotometrically on muscle mitochondrial mitochondrial muscle on rophotometrically
Briefly, mitochondria (0.25 mg protein/mL) protein/mL) mg (0.25 mitochondria Briefly,
monitored simultaneously and calibrated and simultaneously monitored -
3Phosphate (5mM) and Antimycine Antimycine and (5mM) 3Phosphate and io assessed using the commercial kit kit commercial the using assessed quadriceps
µM). µM). (RCR) (RCR) n diinl experimentation additional An t al. et B as substrates. substrates. as F aae n mlt ( and (5 malate and tamate was evaluated by dividing by evaluated was ak cells lank resh
were quickly removed quickly were ( 32 M,ad glutamate, and mM), muscles were kept at at kept were muscles ) - . derived 0.6mM 32 rel, oxygen Briefly, were ). State 4 was 4 State ). State 3 was was 3 State
of H
used for for used 2 H O 2 2 O
raph raph was and and 2 .
9
Version postprint PLS RQ, effectstrai the of examine to used was(ANOVA) varianceof analysisway USA). NC, sd ± Cary, means as provided Inc., are Results Institute (SAS 5.0 version Statview, using performed were analyses Statistical analysis Statistical expressed as ofper per nmoles DOG milligram 15min. ofmuscle incuba the into DOG the of activity specific the by muscle the within radioactivity the dividing by calculated was transport glucose Muscle determination. radioactivity for 80°C at 20min various of presence a or absence the in incubated 2 of 5mM with or without 50nM) and (1 were insulin of concentrations strips muscle transport, glucose assess To assess Saint Aldrich, sodium mM 2 (v/v), glycerol 10% NaF, mM β mM 25 NaPPi, mM 10 EDTA, mM 10 NaCl, mM 150 HEPES, mM (50 RIPA+ various of presence or absence hom and rinsed then were the They minutes. 15 for 50nM) and (1 in insulin of concentrations incubated were strips muscle phosphorylation, Akt assess To the abdominal aorta. Afterfast,an overnight Ex andglucose transport vivoto insulin response muscle GLUT4, at stored and nitrogen liquid in frozen above.described as concentration insulin andglucose ofassay EDTA in collected was Blood injection. after min 30 euthanized and anesthetized then were Mice intraperitoneal an to prior hours 4 for fasted were group per animals Six In vivo insulin muscle response to s described by Dardevet Dardevet bydescribed s mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence D Fisher test was used for post hoc analyses. Results wereD Fishertest forResults washocsignificant post used analyses.at considered the 5%level. Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance lsa eaoie ad hormones and metabolites plasma Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : Ser by western blotting.by western 473 - pAkt - Louis, USA) and 1% Triton X Triton 1% and USA) Louis,
and total Aktcontent. Gastrocnemius 6
animals per group were anaesthetized and euthanized byanaesthetizedeuthanized from andfullbloodredrawing animalsgroup were per et al. et 10.1016/j.freeradbiomed.2017.10.012
Comment citer cedocument:
( 35
) . ; except for the k the for except ;
was cut quickly removed, strips. into They were then rinsed, blotted, weighed and digested in 1 M NaOH for NaOH M 1 in digested and weighed blotted, rinsed, then wereThey -
guoe transport, glucose , 80
°C until quantification of Ser of quantification until °C - - 100) orthovanadate, 0.5% v/v protease inhibitor cocktail (Sigma cocktail inhibitor protease v/v 0.5% orthovanadate,
and a standard western blot procedure was conducted to conducted was procedure blot western standard a and inetic of RQ which is presented as mean ± sem ± mean as presented is which RQ of inetic
biochemical Gastrocnemius
- deoxy -
473 wsen lt n qC assays qPCR and blot western , D n and NAC on bodyon composition, NAC and n
- injection of insulin (0.75mU/g insulin of injection - [ pAkt and total Akt total and pAkt 3
H] glucose (DOG: 0.5μCi/ml) (DOG: glucose H] muscle was quickly removed, was muscle - glycerophosphate, 100 glycerophosphate, in eim i was it medium; tion ogenized in ice in ogenized , as well as well as , - tubes for tubes
. - One cold cold 10 ). ). - - .
Version postprint Glycerol (µmol/l) (µmol/l) Non Triglycerides (g/l) Glucose (g/l) Insulin (ng/ml) Plasma Glycerol (µmol/l) (µmol/l) Non Triglycerides (g/l) Glucose (g/l) Insulin (ng/ml) concentrations in fasted the Plasma state (g) Perirenal adipose tissue Liver (g) Quadriceps Gastrocnemius Body weight (g) Table comparedSAMP8 whereas toSAMR1 compared ( toSAMR1 age, andbody hadsimilar SAMR1 SAMP8 weight, animals for whole body energy metabolism To better comprehenddifferences and strains, between SAMR1 we the SAMP8 first Animals’ body andcomposition, weight andenergymetabolism Results
mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence - - Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance esterified fatty acids esterified fatty acids Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : 1
. Animal characteristics concentrations 30min after ofinsulin* intraperitoneal injection
mass (g)
mass (g)
p<0.0001, p<0.0001,
10.1016/j.freeradbiomed.2017.10.012 0.30 32.7 SAMP8 Comment citer cedocument: 168 109
Table 0.12 14 19 5.6
l 1
iver weight weight iver ).
In , metabolic flexibility , metabolic SAMP8NAC addition, p 0.43 27.8 151 91 but was similar 0.19 7 5.0 16
muscle weights were
erirenaladipose tissue
0.33 32.2
SAMR1 137 198 (
p<0.05, Table and body composition. and body 0.12 18 3.3 16
NAC: p<0.01 p<0.0001Strain: NAC: p=0.01 Strain: NAC: Strain: NAC: p= p= Strain: NAC: p= p= Strain: NAC: p<0.01 p<0.01Strain: NAC: p= p<0.01Strain: NAC: p= p= Strain: NAC: p<0.001 p<0.01Strain: NAC: p= p= Strain: NAC: p= p<0.01Strain: NAC: p= p= Strain: NAC: p= p<0.05Strain: NAC: p Strain: NAC: p= p<0.0001Strain: 15 weight 1 - 2 ). 0
p= p<0.01
% p= p= P valueP characterized the characterized =0.146
0.9 0.327 0.120 0.958 0.692 0.122 0.177 0.240 0.616 0.887 lower in SAMP8 inSAMP8 lower 0.666 0.307 0.211 0.062 0.891 0.104 0.933 was 59% lower was 59%lower
20 At 12month
s
in of 11
Version postprint SAMR1. to higher comparison in a stress oxidative by characterized are mice SAMP8 of muscles that validated we study, our in hypothesized As Oxidative stress is Figure 1. SAMR1 suggestingphases metabolicanimalsa compared flexibilitySAMP8 compared higher toSAMR1, to in kinetics strains for and (0.820±0.037vs.0.807±0.017, respectively SAMR1, SAMP8 and for SAMP8 kJ/24h, respectively SAMR1, calorimetry. energymetabolism, 24h expenditure and respiratory were measured quotient (RQ) indirect using differencesTo explorewere whetherwith alterations energy in these composition inbody associated mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : evidenced (Figure
Respiratory quotient kinetics over 24h quotient o Respiratory Energy expenditure over between 24hsimilar Energy expenditure was t 1 ).
higher that RQ that
in skeletal compared muscle ofSAMP8 toSAMR1
10.1016/j.freeradbiomed.2017.10.012 of SAMP8 of SAMP8 Comment citer cedocument: tended tobelower and inthehigher state fasted inthe and fed
Muscle content in carbonylated protein carbonylated in content Muscle , p= 0.261 f SAMP8 and (n=4f SAMP8 SAMR1 group). per ). RQover 24halsosimilarbetween was two the he two strains (49.4±4.9vs.54.0±4.5 twostrains he
, p= , 0.930 s
was two was ). However
- fold higher in higher fold , 24h 24h
active 12
Version postprint N receiving SAMP8 SAMP8, in group) per (n=10 CoQ10 total (D) and acetylcysteine(SAMP8 CoQ9 total (C) group) 2. Figure comparedcontent was ( higher inSAMP8 toSAMR1 enzymes these of ( SAMR1 to compared SAMP8 in lower 25% was were activity SAMR1 to compared SAMP8 in higher 120% was CoQ10 SAMR1 ( ( SAMR1 to compared SAMP8 p<0.001, mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI :
(
p<0.05 F Muscle content in (A) carbonylated protein (n=4 per group), (B) glutathione (GSH), (n=10 per per (n=10 (GSH), glutathione (B) group), per (n=4 protein carbonylated (A) in content Muscle igure 2 igure similar between the two strains two the between similar , F orbrtd ifrne in differences corroborated B igure igure ) and and ) - NAC) and SAMR1. 3 A a 21% higher glutathione peroxidase activity peroxidase glutathione higher 21% a 10.1016/j.freeradbiomed.2017.10.012 ) .
Comment citer cedocument: M p<0.01, uscle content uscle F igure 2 igure
( F
in aia activities maximal igure A CoQ9 CoQ9 p<0.05, ). This was associated with associated was This ). p<0.01, 3 B and B was F igure igure
similar between similar Table ( 3 p<0.01, D, respectively D, 3 ecp fr Mn for except , C 2 ) ). Strain differences in gene expression gene in differences Strain ). .
Figure in muscle of muscle in
strains ) 2 . D). However content glutathione lower a
- O fr hc mRNA which for SOD C
( tls ad oa SOD total and atalase Figure 2 Figure SAMP8 SAMP8 , Mn , - C) C) SOD activity SOD compared to to compared but that of that but
13 -
Version postprint (p<0.05,SAMR1 Figure to compared SAMP8 in higher 30% being latter the enzyme, the of content protein muscle in differences being latter the the enzymeof expression genein differences by strain corroborated activity oxidasewas Increased xanthine H was mitochondria and oxidase NADPH identifying investigated next We to SAMR1 O (Mn SOD manganese receivingSAMP8 N (C) (tSOD); dismutase superoxide total (B) PX); Figure 3. 2 xidative mu skeletal stress in O mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance 2
Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., production by xanthine oxidase was 70% higher in SAMP8 compared to SAMR1 (p<0.05 SAMR1 to compared SAMP8 in higher 70% was oxidase byxanthine production accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI :
Maximal activityMaximal ofmus
the main source main the 55 - acetylcysteine(SAMP8 od ihr n AP cmae to compared SAMP8 in higher fold whether 5A 10.1016/j.freeradbiomed.2017.10.012 ) which could be related to the higher oxidative stress. oxidative higher the to related be could which .
scle ofSAMP8 is Comment citer cedocument: O production ROS cle antioxidant antioxidant enzymesglutathionecleperoxidase (G (A) similar
- NAC) and (n=10group).NAC) SAMR1 per associated to
between the two strains two the between a icesd n uce f AP mc, n amd at aimed and mice, SAMP8 of muscle in increased was
SAMR1 SAMR1 enhanced xanthine oxidaseenhancedxanthine activity ( <.01 Table p<0.0001,
(Figure - O) () aaae n SAMP8, in catalase (D) SOD); 4
H A and A 2 O 2
production by production
2 4 ) B) ad y strain by and , . By contrast, By . ,
F compared igure igure
both 4 C 14 ). ,
Version postprint acetylcysteine(SAMP8 5. Figure as activity and inthe presencehydrogen (0.6mM) (n=10 incontrol conditions of peroxide group). per (GMS) glutamate/malate/succinate or (GM) xant (C) oxidase; NADPH (B) rotenone; presenceof or absence the in substrates glutamate/malate using chain respiratory mitochondrial 4. Figure mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI :
Total muscle content in (A) xanthine oxidase and (B) GLUT4 in SAMP8, SAMP8 receiving N receiving SAMP8 SAMP8, in GLUT4 (B) and oxidase xanthine (A) in content muscle Total an ore o ratv oye seis n uce f AP ad AR fo (A) from SAMR1 and SAMP8 of muscle in species oxygen reactive of sources Main - NAC) and 10.1016/j.freeradbiomed.2017.10.012 Comment citer cedocument:
SAMR1 (n=8 per group).per (n=8SAMR1
hine oxidase; (D) complex I complex (D) oxidase; hine
15 -
Version postprint Malate dehydrogenase 2 Malate dehydrogenase 1 dehydrogenase 2 glycerol COXIV ND6 ND1 NDUFB8 NDUFB6 respirationMitochondrial PPARbeta PPARalpha Tfam NRF2 NRF1 PGC PGC of Regulation biogenesisand mitochondrial dismutase Mn dismutase 2 Superoxide dismutase 1 Superoxide Catalase Glutathione reductase Glutathione peroxidase 4 Glutathione peroxidase 1 Anti Xanthine oxidase Pro Hypoxanthine Table - - mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Superoxide Superoxide Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance - oxidant enzyme oxidant
- - oxidant enzymes
1beta 1alpha Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI :
2. Muscle gene of expression
-
3
-
phosphate phosphate
- guanine (Hprt). phosphoribosyltransferase
10.1016/j.freeradbiomed.2017.10.012 0.510 0.791 0.769 0.971 0.789 1.005 0.710 1.091 0.851 0.936 0.484 0.621 0.625 0.640 0.818 0.725 0.986 0.759 0.882 10.88 7.05 8.63 2.19 Comment citer cedocument: SAMP8 0.094 0.254 0.295 0.227 0.290 0.308 0.173 1.94 0.153 0.322 0.426 0.172 0.265 2.37 0.240 0.605 0.310 0.263 0.255 0.153 0.108 1.00 2.28
key proteins
functioning SAMP8 0.646 0.808 0.738 0.783 0.376 0.663 0.802 0.570 0.691 0.485 0.958 0.996 0.801 0.492 1.131 0.753 0.918 0.639 1.041 15.45 2.06 6.21 7.27 . Results areResults tothe expressed relative 0.224 0.489 0.224 0.229 0.140 0.286 0.230 1.49 0.149 0.240 0.252 0.210 0.375 0.257 0.171 1.75 0.470 0.479 0.557 0.202 0.323 3.42 - 2.12 NAC
0.04 .852 0.760 0.602 0.814 0.897 0.545 0.749 0.769 0.766 0.864 1.036 0.776 0.849 0.734 0.803 0.747 1.054 0.938 1.069 7.32 7.19 6.85 SAMR1 0.02 0.159 0.354 0.244 0.151 0.220 0.174 0.212 0.175 2.08 0.224 0.321 0.156 0.335 0.215 0.214 1.31 0.184 0.398 0.456 0.244 0.303 2.51
NAC :p=0. Strain : NAC : p<0.05Strain : NAC :p=0. p=0.Strain : NAC :p=0. Strain : NAC :p=0.073 p=0.737Strain : NAC :p=0.798 p=0.488Strain : NAC : Strain : NAC :p<0.0001 p<0.05Strain : NAC : p<0.0001Strain : Strain : Strain : NAC :p=0.1 Strain : NAC :p<0.05 Strain : NAC :p=0. p=0.Strain : NAC :p=0. p=0.Strain : NAC :p=0. p=0.Strain : NAC Strain NAC :p=0.1 p=0.Strain : NAC :p=0.06 Strain : NAC :p=0. p=0.Strain : NAC :p=0. p=0.Strain : NAC Strain NAC :p=0. p=0.Strain : NAC :p=0. p=0.Strain :
housekeepinggene
P valueP : : p<0.05
: p<0.05 : p= p=0.142 p= p= p=0.619 p=0.119 p=0.308 p=0.195 p=0.427 p= p= p= 0.272 0.298 0.889 0.370 0.753 0.200 708 267 299 545 064 943 117 800 471 524 900 535 883 650 690 665 598 708 304 03 66
16
Version postprint kinase 4 Pyruvate dehydrogenase glyceraldehyde 3 Phosphofructokinase GLUT4 Glucose glycolytic uptake and enzymes stimulated IV and contrast groups between similar was stimulated We content between similar is strains Muscle inSAMP8 capacitySAMR1 oxidative compared mitochondrial ishigher to (p<0.01;SAMR1 Figure SAMP8 in higher 60% and Figure (p<0.01; SAMR1 and SAMP8 signi treatment were Mn and content treatment for pre to chose we SAMR1, of characteristics the of miceSAMP8 were withthe antioxydant treated for Since NAC 6months. treatment NAC notalteredany did skeletal in stress oxidative of involvement the investigate to order In Six month both then mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance
Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., infcnl dfeet rm AP ad iia t SM1 ( SAMR1 to similar and SAMP8 from different significantly accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI :
(
, s ,
a
examined whether oxidative stress had an impact on skeletal muscle mitochondrial function. function. mitochondrial muscle skeletal on impact an had stress oxidative whether examined
dehydrogenase ntimycine A/ ntimycine the gene expression expression gene the s tate 3 respiration rate respiration 3 tate in muscle of SAMP8 SAMP8 of muscle in
state 4 respiration rate significantlystate was higher 4respiration ratestate 3respiration of NAC NAC
iaty nrae msl cnet n o9 n CQ0 in CoQ10 and CoQ9 in content muscle increased ficantly - - SOD activity SOD P treatment
as corbate/TMPD/DNP) 2 C andC 10.1016/j.freeradbiomed.2017.10.012 - a wl as well as ,
A oprdt AP,ad3 n 5%i SAMP8 in 253% and 38 and SAMP8, to compared NAC 0.430 0.847 0.870 in SAMP8 8.04 Comment citer cedocument: were reversed after NAC treatment so that that so treatment NAC after reversed were activity the and was 2
(Table of purified mitochondria with substrates of with purifiedsubstrates mitochondria of D). 0.308 0.285 0.288 1.34 22
2
C and C and 24% higher with substrates of complexes II complexes of substrates with higher 24% and
reverses
2
with , tan differences strain ),
1.172 , respect , 2 0.738 0.686 D). Muscle content in CoQ9 and CoQ10 was respectively 20 respectively was CoQ10 and CoQ9 in content Muscle D). substrates 8.44 f atie oxidase xanthine of strain sent only SAMP8 only sent 0.738 0.249 0.254 2.90 ively (p<0.05, (p<0.05, ively
differenc
and RCR significantly andlower RCR of
the in carbonylated protein content, glutathione glutathione content, protein carbonylated in es glycerol 0.545 0.791 0.834 in 7.83 - NAC results for clarity reasons. clarity for results NAC Table 3 Table
skeletal muscle characteristics F which remained unaffected by NAC NAC by unaffected remained which muscle phenotype, both SAM both phenotype, muscle igures igures 0.299 0.207 0.251 2.12 - 3phosphate SAMP8 characteristics of SAMP8 of characteristics
). ). complexes Icomplexes (glutamate/malate)
2 W
and ith ith but - NAC :p<0.05 Strain : NAC :p=0. Strain : NAC :p=0. p=0.Strain : NAC :p=0. p=0.Strain : NAC : all sub all A in NAC
3
mitochondrial mitochondrial shuttle ). in (succinate/rotenone)
- NAC c NAC y otat NAC contrast, By SAMP8 compared compared SAMP8 p= strates p= p =0.370
0.162 oprsn to comparison Tbe 3) (Table 0. 207 270 938 547 831 568 ompared to ompared ,
non
R1 and R1 Except - - ADP NAC ADP ADP . By 17 -
Version postprint (natom O/min/mg prot) Respiration rate A/Ascorbate/TMPD/DNPAntimycine RCR State 4 State 3(natom O/min/mg prot) Glycerol RCR State 4(natom O/min/mg prot) State 3(natom O/min/mg prot) Succinate/Rotenone RCR State 4 State 3(natom O/min/mg prot) Glumate/Malate t differencesin by I complex of inhibition functional a I,suggesting complex of activitycatalytic the inhibits directly peroxide hydrogen that found we (p<0.05, SAMR1 to compared SAMP8 p<0.05, +12%, significance p=0.06, (+14%, SAMR1 to compared SAMP8 in higher be to tended capacity, oxidative mitochondrial the about information provides which activities, synthase SAMP8 from fractions enriched mitochondrial (P<0.05, SAMR1 on to compared higher 30% to 18 was oxidase) c (cytochodrome IV and II complexes and synthase citrate of activity maximal measurements, respiratory with agreement In ND 3 Table treatedabolished in SAMP8 with SAMR1 to , notdetermined. mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance
Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : (natom O/min/mg prot) (natom O/min/mg prot) . - Mitochondrial respiration the ratessubstrates various of using respiratory chain. 3 Phosphate , thus evidencing mitochondrial uncoupling in SAMP8 in uncoupling mitochondrial evidencing thus , when enzyme activities were measured on whole muscle homogenates (SAMP8 vs. SAMR1: SAMR1: vs. (SAMP8 homogenates muscle whole on measured were activities enzyme when he maximal activity of citrate synthase and complexes I, II and IV, were abolished in SAMP8 in IV,abolished were andII I, complexes andsynthase citrate activityof maximal he
al 4 Table
. y otat n srrsnl, aia atvt o cmlx ws 2 lwr in lower 22% was I complex of activity maximal surprisingly, and contrast By ). 10.1016/j.freeradbiomed.2017.10.012 enhanced
Comment citer cedocument: Table 4 Table NAC ( comparedto SAMR1 115.4 19.6 50.7 23.2 SAMP8 6.9 6.3
H Table 4 Table ). Furthermore, the rati the Furthermore, ). 2 2.6 10.9 1.5 O 30.9
2
3
production
). To understand whether understand To ). SAMP8NAC
ND ND ND in
al 4 Table uce of muscle Table 3
o between cytochrome c oxidase and citrate and oxidase c cytochrome between o
(p<0.05, . h dfeec rahs h lvl of level the reaches difference The ). ). 238.7 99.4 18.6 SAMR1 AP (iue 4 (Figure SAMP8 7.0 oxidati 39.1 12.3 6.7 Table 3 Table
ve stress could be the cause the be could stress ve
) . All differences were differences All . Strain: Strain: Strain: p<0.001Strain: p= Strain: NAC: p<0.001 NAC: p<0.001 NAC: p= Strain: P<0.05Strain: P<0.05Strain: Strain: p<0.05Strain: p<0.05Strain: p<0.05Strain: p=0.05Strain: Strain: p<0.05Strain: NAC: p<0.05 NAC: p<0.05 NAC: p<0.01 NAC: p<0.01 D P valueP . Interestingly, ). P=
0.225 0.282 0.820
18 ,
Version postprint Citrate synthase Cytochromec oxidase/ (nmol/min/mg prot) Cytochromec oxidase (nmol/min/mg prot) IIComplex (A.U.) I Complex (nmol/min/mg prot) Citrate synthase enriched fractionMitochondrial rate oxidation Peroxisomal rate oxidation Mitochondrial rate Total oxidation Muscle CREB PGC (nmol/min/mg prot) Citrate mtDNA/nDNA* content mitochondrial Muscle element proliferator content mitochondrial the hand, one the on explored To NDUFA2,NDUFA2 ND6 ( and content results (nucleus). wereand betweenand obtained NDUF1, theratio ND1 using ND1 Similar * mtDNA/nDNAassessed was usingcontent ratio DNA (mitochondria) between the ND6 DNA and NDUF1 4 Table higher inSAMP8 ( SAMR1 to compared NAC with treated further understand the mechanisms underlying the mitochondrial adaptations in muscle of SAMP8, we SAMP8, of muscle in adaptations mitochondrial the underlying mechanisms the understand further
mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance - 1 Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : - P/GAPDH (AU)P/GAPDH synthase
- . Muscle mitochondrial content maximal and enzymes. key oxidative of activity palmitate oxidationfresh tissue/min) rate/g (nmol palmitate /GAPDH (AU) /GAPDH binding protein:
-
activated receptor gamma activated receptor 1 coactivator
- NAC compared to SAMP8 (p<0.05), (p<0.05), andcompared was toSAMP8 NAC t similar
and the protein content of key of content protein the and
CREB 10.1016/j.freeradbiomed.2017.10.012 0.260 0.555 4.98 0.26 3.13 SAMP8 305
Comment citer cedocument: alterations in mitochondrial CoQ content CoQ mitochondrial in alterations - data not shown data not P)
1.41 0.06 1.11 0.041 .
Table 4 Table
SAMP8NAC 0.283 3.54 0.21 2.29 ). 418
). In particular, maximal activity of complex I was 37% was I complex of activity maximal particular, In ). - 0.048 0.42 0.03 0.37 alpha: 71
regulators of mitochondrial biogenesis ( biogenesis mitochondrial of regulators
PGC
0.283 - 3.08 0.22 2.19 1alpha 16.3 SAMR1 393 0.026 0.50 0.05 0.55 2.3 58 , and and o SAMR1 ( o SAMR1
and on the other hand, the muscle muscle the hand, other the on and
phosphorylatedresponse cAMP Strain: p<0.05Strain: NAC: p<0.001 Strain: NAC: p<0.001 Strain: NAC: Strain: NAC: Strain: NAC: Strain: NAC: Strain: valueP NAC: p<0.05 Strain: NAC: p<0.05 p<0.01Strain: NAC: p<0.05 p=0.05Strain: NAC: p<0.01 p<0.05Strain: NAC: p=0.06 p=0.06Strain: NAC: p<0.05 Table 4 p=0.689 p=0.640 p=0.522 p=0.220 p p=0. p=0.414 p=0.101 p=0.183 p=0.350 p=0.06
=0.335 777
).
Peroxisome 19
Version postprint function and biogenesis mitochondrial of regulation the in involved proteins key of expression between similar was content CREB and 1alpha homogenates muscle On receiving SAMP8 SAMP8, N Figure NAC (p<0.0 (Figure (figure CoQ figure (p<0.01; treatment NAC after reduced significantly and strains between CoQ9 total in content Mitochondrial mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : 6 6C .
Total muscle content in (A) CoQ9, (B) CoQ10, (C) CoQ9H2/CoQ9 and (D) CoQ10H2/CoQ10 in CoQ10H2/CoQ10 (D) and CoQ9H2/CoQ9 (C) CoQ10, (B) CoQ9, (A) in content muscle Total ) , 5
whereas 6B ; figure 6A ). - T P content P ). e ai bten eue and reduced between ratio he
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10.1016/j.freeradbiomed.2017.10.012
significantly ( - Table 4 Table tan ad nfetd y A treatment NAC by unaffected and strains acetylcysteine (SAMP8 Comment citer cedocument: ) te ot ersnaie o i mue mitochondria, mouse in CoQ representative most the , , were similar between strains between similar were , lower for CoQ10 in CoQ10 for lower
xdzd om for forms oxidized - NAC) and (n=10 SAMR1 group). per
SAMP8 compared to SAMR1 and SAMP8 and SAMR1 to compared SAMP8 s el as well as
n oprsn o AP ad SAMR1 and SAMP8 to comparison in ,
suggesting that muscle mitochondrial muscle that suggesting CoQ9 . Supporting this conclusion, conclusion, this Supporting mtDNA/n
a smlr ewe strains between similar was DNA ratio
was similar similar was and , (e.g. PGC (e.g. PGC gene total 20 - - -
Version postprint strain di com SAMP8 of muscle skeletal in Akt of rate phosphorylation response t characterizing stress oxidative the that hypothesized Table (p<0.05, SAMR1 to compared concentration glucose plasma fasting lower 30% a by characterized were SAMP8 SAMR1 higher was In vivo muscleAkt phosphorylation compared to beta) receptor activated respectively SAMP8, (p<0.05 SAMP8 in higher 172% and 97 was oxidation, acid fatty mitochondrial 4) isozyme kinase dehydrogenase capacities was This Table3). (p<0.001, 70 ( a demonstrated SAMR1 to compared SAMP8 in lower was palmitate oxidize capacity. oxidative acid fatty their on impact could these Since treatment Muscle acid fatty mitochondrial between oxidative butincre capacityissimilar strains (p<0.05, 2) factor respiratory (Nuclear no and SAMR1, and SAMP8 between similar was 1alpha, mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : intrinsic
fferences were abolished in SAMP8 treatedfferences in SAMP8 were with NAC abolished (p<0.01; Figure PGC
Table 2
n guoe rnpr i seea muscle. skeletal in transport glucose and (p<0.0 the two other groupsthe twoother - 1beta,
adaptations were observed in muscle mitochondria of SAMP8 mice, we questioned whether whether questioned we mice, SAMP8 of mitochondria muscle in observed were adaptations 1 ). ), whereas fasting plasma insulin was similar similar was insulin plasma fasting whereas ), 01
-
3 hge ttl amtt oiaie aaiy oprd o the to compared capacity oxidative palmitate total higher 73% ula rsiaoy atr 1: factor respiratory Nuclear n p<0.05 and similar between SAMP8 and SAMR1 ( SAMR1 and SAMP8 between similar wih peuae PK mRNA PDK4 upregulates which , 10.1016/j.freeradbiomed.2017.10.012 due ,
mRNA content was significantly decreased after NAC after decreased significantly was content mRNA Comment citer cedocument: Table 2 Table ,
to a significant increase in increase significant a to respectively, (p=0.06, , which which , ). In addition, gene expression of PPARbeta ofgene In expression addition, ).
Table 2 Table inhibits the pyruvate dehydrogenase complex and enhances the the enhances and complex dehydrogenase pyruvate the inhibits p<0.05, p<0.05, in stimulationresponse toinsulin Table3). ). NRF1,
afce b NC ramn ( treatment NAC by affected t
Table3). n vivo In neetnl, ee xrsin f PDK4 of expression gene Interestingly, i sri ws soitd ih nacd insulin enhanced with associated was strain his n Mtcodil rncito fco A: factor transcription Mitochondrial and M
both Table 2 Table (35) pared to SAMR1 (p<0.05, Figure (p<0.05, SAMR1 to pared xml capacity aximal
between the two strains (Table 1 (Table strains two the between insulin insulin
Strikingly tne t b hge i SAMP8 in higher be to tended , mitochondrial ). Only peroxisomal activity was 20% 20% was activity peroxisomal Only ). injection - A cmae t SM1 and SAMR1 to compared NAC SM8 rae wt NAC with treated SAMP8 , 7A of muscle homogenates homogenates muscle of in SAMP8 compared to and peroxisomal oxidative peroxisomal and ).
(Peroxisome prolifera (Peroxisome
nue a 3 higher 43% a induced al 2 Table ased after NAC treatment two ). Only NRF2 NRF2 Only ). te gro other
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Version postprint compared15% higherSAMP8 inmuscle (Figure of toSAMR1 Figure respons in SAMR1 to compared SAMP8 in higher 11% to 18 still was It Figure (p<0.001, insulin of 0.2nM of presence the in SAMR1 to compared SAMP8 in higher 26% was Contrastin insulin. of 50nM and 0.2 i.e. insulin, of doses extreme two the at significant not was strains between difference the Figure (p<0.01, respectively insulin, of 5nM and 1 of presence the in SAMR1 to compared (Figure observations vivo Ex treated Figure with NAC 5B). (p<0.05; these and 5B) Figure (p<0.05, SAMR1 to compared SAMP8 (Table treatment NAC by unaffected and strains between similar was metabolism glucose in involved enzymes key of expression gene Muscle to SAMR1 Ex andglucose vivo uptake Akt muscle were phosphorylation muscle higherinskeletal ofSAMP8 compared mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : 7C
nuain f rs msl srp wt icesn dss f nui gv smlr eut to results similar gave insulin of doses increasing with strips muscle fresh of incubation . ial, lcs utk epesd codn t At hshrlto sae a systematically was state phosphorylation Akt to according expressed uptake glucose Finally, ).
g with those latter observations, e observations, latter those with g 7B . ned msl At hshrlto ws 13 was phosphorylation Akt muscle Indeed, ). 10.1016/j.freeradbiomed.2017.10.012
Comment citer cedocument: 2
). By contrast, GLUT4 content was 32% lower in skeletal muscle of muscle skeletal in lower 32% was content GLUT4 contrast, By
x vivo x
glucose uptake measured on fresh muscle strips muscle fresh on measured uptake glucose
strain differences were abolished in SAMP8 in abolished were differences strain 7D ).
e to 1 to 50nM of insulin (p<0.05, insulin of 50nM to 1 to e ad 7 hge i SAMP8 in higher 77% and 5 7B ). However, ). n vivo in 7C 22 ). ).
Version postprint Table (p<0.0001, SAMR1 to compared SAMP8 not did x which gene istheprecursor. dehydrogenase, ofxanthine product same the formis analternate of condition all for SAMP8 phosphorylation corrected not were in Intriguingly SAMP8and receiving 50nM)inSAMP8, N i responseto in transport, deoxyglucose phosphorylationand and Figure anthine oxidase and xanthine dehydrogenase are both able to able both are dehydrogenase xanthine and oxidase anthine mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence ex vivo ex Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : 7 alter .
In vivo
muscle (B) Akt phosphorylation, (C) deoxyglucose transport and (D) relationship between Akt Akt between relationship (D) and transport deoxyglucose (C) phosphorylation, Akt (B) muscle xanthine xanthine these these
and glucose uptake uptake glucose and muscle (A)in responseintraperitoneal Akt toinsulin (0.75mU/g) phosphorylation muscle injection ex vivo vivo ex n AP tetd ih NAC with treated SAMP8 in dehydrogenase/ s, and significantly higher than SAMR1 values SAMR1 than higher significantly and s, 10.1016/j.freeradbiomed.2017.10.012 experimentations Comment citer cedocument: oxidase gene expression expression gene oxidase measured on muscle strips strips muscle on measured
- acetylcysteine(SAMP8 , strain differences strain
2 ),
pr atog te wr abolished were they although , eserved activity of activity eserved ncreasing concentration of insulin (Ins=0.2, 1, 5(Ins=0.2,1, ncreasinginsulin of concentration which produce hydrogen peroxide ( peroxide hydrogen produce
in Akt phosphorylation and glucose uptake uptake glucose and phosphorylation Akt in ee iia bten SAMP8 between similar were - was still was NAC) and (n=6NAC) SAMR1 group). per
( data not shown not data the enzyme the 50 fold higher in NAC in higher fold s
n vivo in may have have may ) . Xanthine oxidase Xanthine 36 . ). Since ). Hence In addition, - resulted in resulted A and NAC - treated , NAC Akt
23
Version postprint but to due that evidenced study Our Discussion and (n=10 SAMR1 group). per N receiving SAMP8 SAMP8, in NAD+, and NADH between ratio the and Figure NADH/NAD lower contentNADHNAD inNADt, and content i To finish, w compared toSAMR1 NADHandNAD content lower inNADt, shows Skeletal muscle of SAMP8 glucose uptake o acute
it mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., also accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : high xidati 8 n SAMP8. We found We thatmusclen SAMP8. ofSAMP8, .
caused inhibition of inhibition caused In vivo In
e examined xanthine oxidase activity oxidase xanthine ve stress during the the during stress ve +
ratio was similar betweensimilar (Figure wasratio all conditions .
muscle content in total NAD (NADt), reduced NAD (NADH), oxidized NAD (NAD+), NAD oxidized (NADH), NAD reduced (NADt), NAD total in content muscle
whetherglucose uptake muscle high NADH with enhanced associated was cytosolic SAMP8 are characte are SAMP8 10.1016/j.freeradbiomed.2017.10.012
Comment citer cedocument: mitochondrial mitochondrial ex vivo vivo ex . H igh ROS production ROS igh incubation thus maintaining high levels of Akt phosphorylation and phosphorylation Akt of levels high maintaining thus incubation +
compounds compared to SAMR1 (p<0.05, compared Figurcompounds toSAMR1 complex I activity. These conflicting These activity. I complex rized by enhanced oxidative stress in skeletal muscle skeletal in stress oxidative enhanced by rized treated or enhanced insulin signaling and and signaling insulin enhanced 8 ). not with not with
NAC + , but similar NADH/NAD , butsimilar - acetylcysteine (SAMP8 acetylcysteine ,
evidenced adaptations
significantly
e 7).However, glucose uptake glucose ,
with regards with +
mainly - ratio ratio NAC) 24
Version postprint oxidasexanthine isconstitutive oxidase xanthine decrease not did treatment NAC However, restor the limiting at helped treatment NAC using cause production ROS of sources intracellular main the of Exploration and SAMP8 SAMP8 that suggest thus results by oxidase xanthine to converted be can dehydrogenase Xanthine precursor. the is which dehydrogenase, xanthine of product gene same the of form content muscle oxidase SAMR1. to compared SAMP8 of muscle in higher 30% was content protein oxidase corrected not was overexpression 55 was expression gene enzyme ( point, as areused h time first the is It mitochondrial metabolism production ROS high to consecutive treatment enhanced second, first, SAMR1: to compared SAMP8 in chain respiration mitochondrial use and production NADH between imbalance resulting the to 38 - 4 mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance 1
ed
Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : of described been has activity oxidase xanthine increased ).
insulin signaling, glucose uptake and mitochondrial functions mitochondrial and uptake glucose signaling, insulin Yet
high high reversed
a model of acceleratedsenescence of model a
n mtcodil ope I activity I complex mitochondrial and n AP mice SAMP8 in respiratory ROS ROS
complex igh xanthine oxidase expression oxidase xanthine igh all production in skeletal muscle of of muscle skeletal in production - NAC. SAMP8 SAMP8 was corrected was
chain function h ratio the 10.1016/j.freeradbiomed.2017.10.012
es
, the the , Comment citer cedocument: lyenhanced II characteristics - fold higher in higher fold by and ewe xnhn oiae n xnhn dhdoeae a dfe by differ may dehydrogenase xanthine and oxidase xanthine between
increased activity of xanthine oxidase oxidase xanthine of activity increased 6 months of NAC treatment. NAC of months 6
.
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activity in 6 months of NAC treatment NAC of months 6
muscle of and especially, of muscular aging ( aging muscular especially,of and impact of high high of impact o SAMR1 to may skeletal muscle of muscle skeletal and and is reported is help is AP mice. SAMP8 associated associated partially SAMP8
at n uce f SAMP8 of muscle in
, including hydrogen peroxide ( peroxide hydrogen including ,
preserving metabolic flexibility.preserving metabolic values w ROS in ith aging ith
, mice.
sugg
opnae b itisc dpain of adaptations intrinsic by compensated Corroborating activity; skeletal muscle of SAMP8 mice SAMP8 of muscle skeletal spotn ta tee dpain were adaptations these that supporting , were
eprto rate respiration SAMP8 compared to SAMR1 and this this and SAMR1 to compared SAMP8 rdcin n uce eaoim and metabolism muscle on production Enhancing ests that ests
of these animals these of soitd ih dutet in adjustments with associated in skeletal in . Xanthine oxidase is an alternate an is oxidase Xanthine .
uprig u hptei that hypothesis our supporting mitochondrial s likely is xanthine oxidase xanthine the latter the
, 37
h anti the ROS ROS s )
muscle this with Inagreement . . Surprisingly osiuie ic the since constitutive Six Six impact to
xdn protection oxidant
analysis, xanthine analysis, ots f NAC of months uncoupling,
4 SAMR1
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. Our present Our . other models other n glucose on is the main the is , . SAMP8 . xanthine
values
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Version postprint strain. P8 the in use glucose enhanced an suggesting SAMR1, to compared SAMP8 in similar, production NADH by caused metabolism NADH for adaptation an from result may SAMP8 insulin. supra and physiological of presence the in as well as absence the in SAMR1, that showed study I production.ROS SAMP8, in treatment NAC complex of activity to relate mainly complexes. NRF CREB, 1beta, observe mit CoQ10 and CoQ9 since of involvement shuttle, dehydrogenase SAMR to compared SAMP8 in higher mitochondrial i the of part that in agreementwith Echtayal. ( et in activity rate respiration IV mitochondrial and II complexes of activity maximal higher SAMP8 in higher significantly were A/Ascorbate/TMPD/DNP content. not but function h SAMP8, of muscle skeletal In areet ih rvos reports previous with agreement n mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : We thus hypothesized that the enhanced mitochondrial respiration capacity observed in muscle of of muscle in observed capacity respiration mitochondrial enhanced the that hypothesized thus We changes
SAMP8 Therefore,
nopig Indeed, uncoupling. mitochondrial CoQ content CoQ mitochondrial
in the expression of major regulators of mitochondrial biogenesis (i.e. PGC (i.e. biogenesis mitochondrial of regulators major of expression the in mitochondrial . Our hypothesis was supported by a reduced b reduced a by supported was hypothesis Our . ,
tisc dpain o te mitochondr the of adaptations ntrinsic ex vivo vivo ex - suggesting I , NRF 1, .
Since
our our respectively. 10.1016/j.freeradbiomed.2017.10.012 our study our uce lcs utk was uptake glucose muscle ochondrial contents were similar between the two strains. two the between similar were contents ochondrial obnd aa ugs that suggest data combined - all strain differences in mitochondrial function were corrected by 6 months of months 6 by corrected were function mitochondrial in differences strain all , fm n PAs a wl a ta o ky subunit key of that as well as PPARs) and Tfam 2, M Comment citer cedocument:
a balancing mechanism mechanism balancing a was was nopig icesd opee I t I activity IV to II complexes increased uncoupling, tcodil eprto rate respiration itochondrial 4 3 igh ) who thatactivat demonstrated ROS non similar between the two strains strains two the between similar hc eiecd that evidenced which
otatn wt tee bevtos o observations, these with Contrasting support 1 using substrates of complex I, complex complex I, complex of substrates using 1 ROS production production ROS - ADP stimulated state 4 respiration rate was was rate respiration 4 state stimulated ADP
in the adaptations of mitochondrial respiration of SAMP8 mice SAMP8 of respiration mitochondrial of adaptations the in s
that that these . Intriguingly with a ascae with associated was 15% mitochondrial adaptations mitochondrial mitochondrial adaptation adaptation mitochondrial O ehne lcs utk ( uptake glucose enhance ROS
the a rsiain chain respiration ial
higher
ih ucnt/oeoe n Antimycine and succinate/rotenone with oprdt SAMPR1 to compared enhanced
asal glycemia, whereas insulinemia was was insulinemia whereas glycemia, asal ih h sbtae glutamate/malate substrates the with despite despite n average on e uncoupling proteins, enhanced glycolysi enhanced
complex IV activity IV complex - physiological concentration of concentration physiological ad r aa i nt upr the support not did data ur lower a II a
ptations and glycerol and n AP cmae to compared SAMP8 in
was and and are n uce f SAMP8 of muscle in s of respiratory chain chain respiratory of s
5 59 35,
We We ope I catalytic I complex , in agreement with agreement in ,
consecutive to high to consecutive decreased
du in 14 further failed to failed further t enhanced to e s and cytosolic and s - our data show data our mitochondrial ad 2 and % ) 1alpha, PGC 1alpha, , - .
3 The malate The In addition In our our - phosphate phosphate
intrinsic present - fold fold 26 - - , ,
Version postprint adaptation. this in ROS of involvement the supporting values, SAMR1 to response treatment Furthermore,NAC SAMR1. to compared SAMP8 in higher ( Interestingly, higher period RQduring nutritional to adapts still meta preserving at help may maintained SAMP8 was capacity oxidative acid fatty that demonstrate they since important are observations H ligands known its of none since unclear is PPARbeta of involvement The identified. be to remain expression enhanced PDK4 for al. increased wascapacity oxidative acid fatty SAMR1, to compared SAMP8 in c oxidative chain acid fatty mitochondrial respiratory the of adaptations positive the with Contrasting NADH metabolism adapt intrinsic that suggest treatment, lower significantly SAMR1, was NADH in content muscle addition, In SAMR1. and However, ( obesity to resistance two equivale glycerol the and aspartate 16 2
O ) (
4 mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance 2 who ytm hv be ivle i svrl iutos f eaoi ajsmn t hg ft it ( diet fat high to adjustment metabolic of situations several in involved been have systems
8 Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : ( ) 50 , gene analyses suggest that PDK4 could be involved in this adaptation. Yet, the factors responsible factors the Yet, adaptation. this in involved be could PDK4 that suggest analyses gene , nts of cytosolic NADH into the mitochondria to power the complexes I and III, respectively III, and I complexes the power to mitochondria the into NADH cytosolic of nts despite high glycolytic activity, suggesting that mitochondrial adaptations to high ROS production production ROS high to adaptations mitochondrial that suggesting activity, glycolytic high despite
) whereas NADH/NAD whereas evidenced that ROS enhance insulin sensitivity enhance insulin ROS that evidenced
, both although or muscle even complex I complex
but rather to ROS production but rather toROS oxidized lipids lipids oxidized all were insulin signaling insulin 4 5 other s offeeding activity and ) in rodents, as well as to ca to as well as rodents, in ) transitions -
specifically enhanced in in enhanced specifically 3 and 10.1016/j.freeradbiomed.2017.10.012 tos f h mtcodil eprtr can o o rsl fo ajsmn to adjustment from result not do chain respiratory mitochondrial the of ations - phosphate dehydrogenase shuttles are both involved in the transfer of reducing of transfer the in involved both are shuttles dehydrogenase phosphate bolic flexibility. bolic ifrne i mtcodil ucinn wr. hs cmie rsls thus results combined These were. functioning mitochondrial in differences Comment citer cedocument: glycerol +
ratio was simil was ratio
in SAMP8, with a tendency for a lower RQ during fasting periods and a a and periods fasting during RQ lower a for tendency a with SAMP8, in apacity was similar between the two strains two the between similar was apacity ( 5 1 - varied as the mitochondrial function mitochondrial the as varied ) 3
ht a aie rm h frt w conditions two first the from arise may that Phosphate
by 70% in SAMP8 in 70% by This hypothesis is supported by the fact that whole body whole that fact the by supported is hypothesis This ar. Finally, t Finally, ar.
. in comparison S to in
SAMP8 - related respiration respiration related loric restriction ( restriction loric , in vivo in - hese strain differences were not altered by NAC by altered not were differences strain hese NAC compared to SAMP8, i.e. SAMP8, to compared NAC
treated with NAC with treated and AMR1. in vitro in in SAMP8 in 4 rates were rates 6 ) and stress ( stress and )
. muscle responseto muscle I n agreement with agreement n . In addition, mitochondrial addition, In . . restored the restored As proposed by proposed As
n AP cmae to compared SAMP8 in similar between SAMP8 between similar This has been associated been has This . 4
7 eetees these Nevertheless, ) in other models. other in ) fatty acids ( acids fatty in vivo in insulin was insulin
Loh Randle 4
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Version postprint to answer thisquestion. is mechanism mimetic muscle skeletal re insulin in differences by explained be (p<0.01) SAMR1 to compared SAMP8 in higher 56% was glycemia injection insulin after obtained those with little but state fasted the in obtained results Finally glucoseenhanced uptake surface cell decreasedin is insulin. to response tissue the reflect not does tissue the in content total GLUT4 that or expression GLUT4 protein in adaptations specific present may model SAMP8 the that suggests This strains. between altered significantly not was content mRNA GLUT4 prote nuclear of 3T3 lineage D Pessler muscle. skeletal in before reported been not has This values. SAMR1 to content this increased significantly treatment NAC that compared SAMP8 of muscle in lower 32% was content GLUT4 that found we Interestingly, indirectly,related. mitochon that arguments additional provides study NAC in values SAMR1 to decreased are both and SAMR1, to compared functions A Akt as such pathway, signaling insulin the of targets downwards of state phosphorylation enhanced ROS to daptations mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : , - mediated inhibition of phosphata of inhibition mediated the the whereas Furtherm . -
higher glucose uptake in muscle of SAMP8 compare to SAMR1 is consistent with the the with consistent is SAMR1 to compare SAMP8 of muscle in uptake glucose higher L1 that oxidative stress causes decreased GLUT4 expression, associated with impaired binding impaired with associated expression, GLUT4 decreased causes stress oxidative that L1 n h isln inln pathway signaling insulin the in hog a hshtdlnstl 3 phosphatidylinositol a through however muscle of muscle ins to the insulin responsive element in the GLUT4 promoter. However in the present study, present the in However promoter. GLUT4 the in element responsive insulin the to ins takes takes
n h ohr hand, other the on o e mtcodil ucin n isln estvt ae nacd n AP mice SAMP8 in enhanced are sensitivity insulin and function mitochondrial re, up up
unknown since we did not explore liver metabolism liver explore not did we since unknown .
SAMP8, it is known that oxidative stress can stimulatecanstress thatoxidative known is it SAMP8, hg aon o glucose of amount high a 10.1016/j.freeradbiomed.2017.10.012 Comment citer cedocument: h lvr a b isln eitn de o nte mechanism another to due resistant insulin be may liver the ses such as PTP1B, PTEN, PP2A and MAPKAP and PP2A PTEN, PTP1B, as such ses pne bet sponse
- kinase r idpnet rm hs observed those from independent are drial function and insulin signaling are closely, are signaling insulin and function drial en kltl uce n lvr O te n hand, one the On liver. and muscle skeletal ween - mainly mainly eedn pathway dependent et al. et eas hdoe prxd at a insulin as acts peroxide hydrogen because proteolysis.
(52) have demonstrated in the adipocyte the in demonstrated have (52) . We propose that the discrepancy may discrepancy the that propose We . -
treated SAMP8. Therefore, SAMP8. treated and further studies are required are studies further and (53)
Nevertheless, it is well knownwell is it Nevertheless, GLUT4 translocation a translocation GLUT4 is a surprising result which result surprising a is
thus Even if Even
since in that situation, situation, that in since otiuig o the to contributing - in 1, resulting in an an in resulting 1,
GLUT4 content GLUT4 to mitochondrial SAMR1 and SAMR1 although in vivo in . ( T t thet
13 our the the his 28 ) .
Version postprint There of interest conflict isno be to declared. Declaration interest of from Unitfor their the Humanskillful Nutrition Jouve, Chrystele thank authors The Acknowledgements a grantF from the funding ANSSD an through particular in INRA, institution authors' the by supported was work The Funding capacityand metabolic flexibility compar activity, I complex subdued but activity, oxidative mitochondrial and uptake glucose sensitivity, x high to due SAMR1 summary, In mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle ofsenescence Rieusset, J.,Morio,B. (Auteurdecorrespondance) (2017). Reactive oxygenspecies enhance Barquissau, V.,Capel, F.,Dardevet,D., FeilletCoudray, C.,Gallinier ,A.,Chauvin, M.-A., accelerated prone mice SAMP8. Free Radical Biology and Medicine, 113, 267-279. DOI : ed
to SAMR1. We propose that these these that propose We SAMR1. to AP ae hrceie b ehne oiaie tes n kltl uce n oprsn to comparison in muscle skeletal in stress oxidative enhanced by characterized are SAMP8 rench SocietyDiabetesrench ofFrancophone (Société SFD). duDiabète,
anthine oxidase activity. High ROS production production ROS High activity. oxidase anthine 10.1016/j.freeradbiomed.2017.10.012
Comment citer cedocument: which of animals matches SAMR1 those hitpe Montaurier, Christophe
ROS
technical assistance. - driven adaptations help at help adaptations éoiu Pta ad Jean and Patrac Véronique
. eut in results
preserving
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