Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy

nutrients

Review Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy

Yanan Wang 1 , Qing Liu 2, Helong Quan 3, Seong-Gook Kang 4 , Kunlun Huang 1,5,* and Tao Tong 1,*

1 Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; [email protected] 2 Jilin Green Food Engineering Research Institute, Changchun 130022, China; [email protected] 3 Exercise and Metabolism Research Center, College of Physical Education and Health Sciences, Zhejiang Normal University, 688 Yingbin Avenue, Jinhua 321004, China; [email protected] 4 Department of Food Engineering, Mokpo National University, Muangun 58554, Korea; [email protected] 5 Key Laboratory of Safety Assessment of Genetically Modiﬁed Organism (Food Safety), Ministry of Agriculture, Beijing 100083, China * Correspondence: [email protected] (K.H.); [email protected] (T.T.)

Abstract: Imbalance of protein homeostasis, with excessive protein degradation compared with protein synthesis, leads to the development of muscle atrophy resulting in a decrease in muscle mass and consequent muscle weakness and disability. Potential triggers of muscle atrophy include inﬂammation, malnutrition, aging, cancer, and an unhealthy lifestyle such as sedentariness and high fat diet. Nutraceuticals with preventive and therapeutic effects against muscle atrophy have recently received increasing attention since they are potentially more suitable for long-term use. The implementation of nutraceutical intervention might aid in the development and design of precision medicine strategies to reduce the burden of muscle atrophy. In this review, we will summarize the current knowledge on the importance of nutraceuticals in the prevention of skeletal muscle mass loss and recovery of muscle function. We also highlight the cellular and molecular mechanisms of Citation: Wang, Y.; Liu, Q.; Quan, H.; these nutraceuticals and their possible pharmacological use, which is of great importance for the Kang, S.-G.; Huang, K.; Tong, T. prevention and treatment of muscle atrophy. Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy. Keywords: muscle atrophy; protein synthesis/degradation; molecular mechanisms; nutraceuti- Nutrients 2021, 13, 1914. https:// doi.org/10.3390/nu13061914 cal; phytochemical

Academic Editor: Matteo Tosato

Received: 28 April 2021 1. Introduction Accepted: 31 May 2021 Muscle atrophy is a worldwide chronic progressive muscle disease due to excessive Published: 2 June 2021 protein degradation versus protein synthesis. It is characterized by muscle mass loss, muscle weakness, and disability, all of which are associated with an impaired quality of Publisher’s Note: MDPI stays neutral life [1]. Various stimuli, such as aging, genetics, denervation, starvation, unhealthy lifestyle with regard to jurisdictional claims in (i.e., sedentariness, high fat diet (HFD)), systemic pathologies (i.e., diabetes, inflammation, published maps and institutional affil- cancer), and long-term drug therapy (i.e., glucocorticoids) are known to further skeletal iations. muscle loss and weakness [2–4]. On one hand, the increase in life expectancy and the elderly population, in conjunction with the high prevalence of muscle atrophy in the elderly, create an enormous socioeconomic burden. On the other hand, despite its broad clinical impact, skeletal muscle atrophy is a relatively understudied and underdeveloped area of Copyright: © 2021 by the authors. biomedical research and still lacks effective pharmacological therapy, which pointing to a Licensee MDPI, Basel, Switzerland. large need for effective and new anti-atrophy approaches. This article is an open access article Molecular investigations of skeletal muscle atrophy have primarily focused on the distributed under the terms and atrogin-1/muscle atrophy F-box (MAFbx) and E3 ubiquitin ligases muscle RING finger conditions of the Creative Commons 1 (MuRF1) [5]. MuRF1 binds to myosin heavy chain (MHC) and myofibrillar protein Attribution (CC BY) license (https:// titin, resulting in skeletal muscle loss [6]. Mice deficient in either MAFbx or MuRF1 were creativecommons.org/licenses/by/ demonstrated to be resistant to atrophy [7]. Under a wide range of conditions including 4.0/).

Nutrients 2021, 13, 1914. https://doi.org/10.3390/nu13061914 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, x FOR PEER REVIEW 2 of 41

demonstrated to be resistant to atrophy [7]. Under a wide range of conditions including starvation, muscle disuse, glucocorticoid excess, and aging, the glucocorticoid receptor Nutrients 2021, 13, 1914 2 of 36 and transcription factor forkhead box O (FoxO) increase the expression of MuRF1 and promote muscle atrophy [5]. Moreover, proinflammatory cytokines present in the muscle trigger the nuclearstarvation, factor muscle κ-light-chain-enhancer disuse, glucocorticoid of excess, activated and aging, B cells the glucocorticoid(NF-κB) signaling receptor pathways to mediateand transcription muscle factor degradation forkhead box [8,9]. O (FoxO) Oxidative increase stress, the expression characterized of MuRF1 andby increased reactivepromote oxygen muscle species atrophy [(ROS)5]. Moreover, production proinﬂammatory and impairment cytokines present of antioxidant in the muscle defense systems,trigger is also the nucleara major factor triggerκ-light-chain-enhancer of imbalance between of activated protein B cells (NF-synthesisκB) signaling and pathways to mediate muscle degradation [8,9]. Oxidative stress, characterized by increased degradation leadingreactive to oxygen muscle species atrophy (ROS) [10,11] production. Myostatin, and impairment a member of antioxidant of the transforming defense systems, growth factor-βis (TGF- also a majorβ) superfamily trigger of imbalance and critical between autocrine protein synthesis inhibitor and degradationof skeletal leadingmuscle to growth, inducesmuscle muscle atrophy fiber [10 ,11atrophy]. Myostatin, by athe member activation of the transforming of Smad2 growth and factor-Smad3β (TGF- andβ) suppresses proteinsuperfamily synthesis and by critical the inhibition autocrine inhibitor of protein of skeletal kinase muscle B (Akt) growth, (Figure induces 1). On muscle the contrary, the activationﬁber atrophy of byinsulin-like the activation growth of Smad2 factor and (IGF-1)/phosphoinositide Smad3 and suppresses protein 3-kinase synthesis by the inhibition of protein kinase B (Akt) (Figure1). On the contrary, the activation (PI3K)/Akt signalingof insulin-like pathway growth represses factor (IGF-1)/phosphoinositide the MAFbx and MuRF1 3-kinase gene (PI3K)/Akt expression signaling via decreasing the expressionpathway represses and activity the MAFbx of andFoxO. MuRF1 In addition gene expression to inhibiting via decreasing muscle the atrophy, expression the activation ofand insulin-like activity of FoxO. growth In addition factor to 1 inhibiting (IGF-1)/PI3K/Akt muscle atrophy, pathway the activation also ofstimulates insulin-like protein synthesisgrowth and factorinduces 1 (IGF-1)/PI3K/Akt muscle growth pathway via rapamycin also stimulates complex protein (mTOR) synthesis kinase and induces [5]. muscle growth via rapamycin complex (mTOR) kinase [5]. Recently, gut microbiota has Recently, gut microbiotabeen proposed has as been an environmental proposed factoras an involved environmental in the regulation factor of involved host immunity in the and regulation of hostmuscle immunity metabolism and [12 muscle,13]. Understanding metabolism the [12,13]. change inUnderstanding the signaling pathways the change during in the signalingthe pathways development during of muscle the atrophy devel mayopment lead to of identifying muscle andatrophy developing may therapeutic lead to identifying andagents developing for muscle therapeu atrophy.tic agents for muscle atrophy.

FigureFigure 1. Cellular 1. andCellular molecular and mechanisms molecular regulating mechanisms muscle regulating growth and atrophy.muscle Akt, growth Protein and kinase atrophy. B; FFAs, Akt, Free fattyProtein acids; FoxO,kinase Forkhead B; FFAs, box Free O; IGF-1, fatty Insulin-like acids; FoxO, growth Forkhead factor 1; MAFbx, box O; Muscle IGF-1, atrophy Insulin-like F-box; MHC, growth Myosin factor heavy 1; chain;MAFbx, mTOR,Muscle Mammalian atrophy target ofF-box; rapamycin; MHC, MuRF1, Myosin Muscle heavy RING-ﬁnger chain; protein-1; mTOR, MyoD, Mammalian Myogenic differentiationtarget of rapamycin; antigen; NF-κB,MuRF1, Nuclear factorMuscle kappa-B; RING-finger PI3K, Phosphoinositide protein-1; MyoD, 3-kinase; Myogenic P70S6K, Ribosomal differentiation protein S6antigen; kinase; ROS,NF-κ ReactiveB, Nuclear oxygenfactor species; kappa-B; 4E-BP1, Rapamycin PI3K, Phosphoinositide complex and 4E binding 3-kinase; protein-1. P70S6K, Ribosomal protein S6 kinase; ROS, Reactive oxygen species; 4E-BP1, Rapamycin complex and 4E binding protein-1.

Experimental models used for muscle atrophy studies mainly contain HFD-, cancer-, denervation-, glucocorticoid-, and disuse-induced muscle atrophy model. The mechanisms inducing muscle atrophy between the numerous models presented are not identical. For example, the mechanisms underlying HFD-induced atrophy are not fully understood, but recent experimental data suggest that multiple factors such as elevated levels of toxic lipid metabolites and pro-inflammatory cytokines may contribute to a decrease in muscle mass and strength [14]. The pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6), and interleukine-1 (IL-1), have long been considered as mediators of cancer-induced muscle atrophy [1]. Enhanced generation of mitochondrial ROS may be a common factor in the mechanism underlying denervation-induced atrophy [15]. Although the exact mechanism underlying glucocorticoid-induced skeletal muscle atrophy is unclear, it is considered to be multifactorial and is related to decreased protein synthesis, increased protein degradation, alterations in carbohydrate metabolism, oxidative stress, and/or decreased sarcolemmal excitability [16]. Evidence from various preclinical studies has revealed that nutraceuticals play a significant role in maintaining muscle health and emerge as potential therapeutic agents in a broad range of muscle atrophy models [17,18]. For example, polyphenols, flavonoids, alkaloids, and probiotics show beneficial regulatory effects on muscle cells or tissues and they seem to be potentially more suitable for long-term use than traditional therapeutic agents. Here, this review highlights current knowledge and recent advances in understanding the impact of various nutraceuticals on skeletal muscle atrophy. We also will discuss their underlying molecular mechanisms in the prevention of muscle mass loss and recovery of muscle function.

2. Materials and Methods Research articles that focused on the nutraceutical intervention for muscle atrophy and the mechanisms of muscle atrophy were collected using various search engines including PubMed, Web of Science, Scopus, Google Scholar, Springer, and Wiley. The keywords such as muscle atrophy, protein synthesis/degradation, molecular mechanisms, nutraceutical, nutrient, oxidative stress, muscle mass, muscle strength, microbiota, glucocorticoid, and phytochemical were used. The articles identiﬁed were reviewed and relevant citations within these articles were also reviewed.

3. Dietary Nutrients Currently, there is increasing preclinical data and evidence that dietary nutrients supplementation can protect skeletal muscle from atrophy damage. In this part, we will summarize the existing scientiﬁc evidence gleaned from a variety of in vitro/vivo studies that supports the beneﬁcial impacts of dietary nutrients on the skeletal muscle atrophy.

3.1. Protein, Amino Acid, and Peptides The most obvious feature of skeletal muscle atrophy is the loss of muscle protein due to the imbalance between decomposition of muscle protein and the synthesis of muscle protein. Protein, amino acid, and peptides supplementation (Table1) is considered to be effective in increasing muscle anabolism and preventing muscle atrophy during extended periods of immobilization [19]. Oral administration of a high protein liquid nutritional supplement (milk protein, whey protein, leucine, and citrulline) inhibits intermittent loading- induced muscle atrophy and increases muscle mass by activating the mTORC1 signaling pathway (Ribosomal protein S6 kinase (p70S6K) and ribosomal protein S6 (rpS6)) [20]. Shin et al. reported that soluble whey protein hydrolysate increases grip strength, muscle mass, and cross-sectional area of muscle ﬁber and meliorates immobilization-induced C57BL/6 mice muscle atrophy via regulating the PI3K/Akt pathway [21]. Leucine promotes muscle protein synthesis in C2C12 myotubes through the activation of mTOR and rapamycin complex and 4E binding protein-1 (4E-BP1) signaling pathway, a critical intracellular pathway involved in the regulation of muscle protein synthesis [22]. Meanwhile, Dreyer Nutrients 2021, 13, 1914 4 of 36

et al. found that following resistance exercise leucine-enriched essential amino acid and carbohydrate ingestion enhances mTOR signaling and protein synthesis in human leg muscle [23]. In addition, supplementation of leucine can offset anabolic resistance and increases muscle protein synthesis in old women [24]. Combined resistance training with essential amino acid mixture (L-isoleucine, L-histidine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, and L-valine) supplementation protects against the losses of muscle mass and strength in man during 28 days of bed rest and energy deficit [25]. In cachexia-inducing tumor Naval Medical Research Institute mice with a significant suppression in the loss of body weight, leucine or valine could increase protein synthesis and attenuate the increased protein degradation [26]. Similar to leucine and valine, isoleucine acts as an intermediate to drive muscle protein synthesis and reduce the rate of protein breakdown [27]. Branched-chain amino acids (22.9% L-isoleucine, 45.8% L-leucine, and 27.6% L-valine) have been shown to inhibit hindlimb suspension-induced muscle atrophy in Sprague Dawley (SD) rats via, at least in part, suppressing the expression of MAFbx and MuRF1 in soleus muscles [28]. The supplementation of amino acid complex (leucine: isoleucine: valine = 2:1:1; 3% in tap water) ameliorates angiotensin II-induced muscle atrophy and increases skeletal muscle weight and gastrocnemius tissue cross-sectional area [29]. Similarly, a study showed that before the inactive phase of rat micellar casein and whey protein (1:1) supplementation increase muscle protein synthesis due to increased plasma levels of branched-chain amino acids and the activation of the downstream targets of mTOR signaling [30]. D-methionine, an amino acid commonly found in fermented dairy products like cheese and yogurt, increases gastrocnemius muscle and soleus muscle weight in cisplatin-induced Wistar rats muscle atrophy model. The protective effect of D-methionine is associated with the downregulation of the expressions of MAFbx and MuRF1 and the upregulation of the expressions of myogenin and myogenic differentiation antigen (MyoD) [31]. In addition, dietary supplement with high level methionine (1.25%) significantly increases the muscle total cross-sectional area of the juvenile rainbow trout (Oncorhynchus mykiss)[32]. In the broilers the high level of methionine diets increases breast muscle growth by increasing the mRNA levels of myogenic regulatory factors such as myogenic regulatory factors 4 and myogenic factors 5 and decreasing myostatin mRNA level [33]. Glutamine is an important amino acid with many functions in the body, such as stimulating protein-synthetic and inhibiting protein-degradative signaling pathways in skeletal muscle of diabetic rats [34]. L-glutamine improves C2C12 cells differentiation and prevents TNF-α-induced myotube atrophy via reducing p38 mitogen-activated protein kinase (MAPK) signal transduction [35]. Oral L-glutamine pretreatment attenuates 24-h fasting-induced muscle atrophy in C57BL/6 mice [36]. Moreover, glutamine supplementation prevents glucocorticoid-induced SD rats skeletal muscle atrophy and increases muscle mass, partially through inhibiting the expression of myostatin. Similarly, in C2C12 myoblast cells, glutamine treatment prevents the hyperexpression of myostatin induced by dexamethasone [37]. Taurine, a containing sulfur nonessential amino acid, is widely distributed in different tissues in particular in skeletal muscle and prevents muscle atrophy in vitro and in vivo. In C2C12 myotubes, Stacchiotti et al. reported that taurine rescues cisplatin-induced muscle atrophy by restoring microtubular and mitochondrial function and reducing the overload and the localization of autophagolysosomes [38]. Intraperitoneal administration of taurine to albino mice every day for 1 week alleviates muscle atrophy induced by reduced mechanical loading through downregulating MuRF1 and caspase 3 expression in quadriceps muscle [39]. Furthermore, oral supplementation of taurine attenuates diquat- induced muscle damage and suppresses the gene expression of muscle atrophy-related genes (MAFbx and MuRF1) in the skeletal muscle of piglets [40]. Dietary supplementation of creatine in tumor-bearing Wistar rats prevents muscle atrophy via alleviating inflammation and proteolysis as evidenced by reduced inflammation factor (TNF-α and IL-6) and muscle atrophy gene (MAFbx and MuRF1) [41]. In a separate Nutrients 2021, 13, 1914 5 of 36

study, Marzuca-Nassr et al. reported that oral gavage of creatine to Wistar rats increases the muscle mass and the protein level of 4E-BP1 in extensor digitorum longus and prevents hindlimb suspension-induced muscle atrophy [42]. S-allyl cysteine (SAC) is an organosulfur compound of Allium sativum, possessing immuno-and redox-modulatory broad-spectrum properties. Gupta et al. reported that SAC suppresses the rise in cytokines levels (TNF-α, IL-6, and myostatin) and protects myotubes from H2O2-induced protein loss in C2C12 myotubes. They also demonstrated that SAC alleviates mass loss and increases cross-sectional area of muscle on Swiss albino mice [43]. Those results illustrate that SAC significantly inhibits the proteolytic systems and inflammatory/oxidative molecules and therefore play a crucial role in the prevention of skeletal muscle atrophy. In addition to protein and amino acids, diet contain multiple bioactive peptides have been shown to prevent muscle atrophy. For example, dietary supplementation of small molecular weight soybean protein-derived peptides attenuates burn injury-induced muscle atrophy in Wistar rats by modulating ubiquitin–proteasome system and autophagy signaling pathway [44]. PYP1-5, a Pyropia yezoensis peptide, inhibits muscle atrophy induced by dexamethasone through the downregulation of MAFbx and MuRF1 in C2C12 myotubes [45]. There are also some experimental muscular atrophy-related therapies based on the use mimetic peptides. For example, N-myristoylated Cblin, a peptide mimetic of tyrosine, inhibits dexamethasone-induced atrophy in C2C12 myotubes and increases gastrocnemius muscle wet weight and cross-sectional area in dexamethasone-treated C57BL/6 mice. The primary mechanism is associated with the downregulated expression of MAFbx and MuRF1 [46]. Laminin mimetic peptide nanofibers significantly promote the activation of satellite cell in skeletal muscle and accelerate the regeneration myofibrillar following acute muscle injury in SD rats [47]. Succinate, a vital intermediate in the tricarboxylic acid cycle, has been reported to play an important role in the process of muscle. Succinate supplementation interferes myoblast differentiation, characterized by significant decreases in the later markers of myogenesis and fewer nuclei per myosin heavy chain positive structure in C2C12 cells. Furthermore, recent studies demonstrated that orally administration of 2% succinate impairs muscle regeneration in FVB mice [48]. Nutrients 20212021,, 1313,, xx FORFOR PEERPEER REVIEWREVIEW 6 6 ofof 4141

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Table 1. Protein, amino acids, and peptides in the prevention of the muscle atrophy in vitro/vivo. Table 1. Protein, amino acids, and peptideses inin thethe preventionprevention ofof thethe muscle atrophy in vitro/vivo. Protein/Amino Protein/Amino Structure Example Source Inducer Model Effect Mechanism Ref Acids/Peptides Structure Example Source InducerInducer Model Effect Mechanism Ref Acids/Peptides ↑ GripGrip↑ Grip strengthstrength strength ↑ ↑ Muscle mass Whey protein / Egg, meat, milk Immobilization C57BL/6 mice ↑ MuscleMuscle massmass ↑ mTOR signaling [21] Whey protein // Egg, meat, milk ImmobilizationImmobilization C57BL/6 mice ↑ Cross-sectional ↑ mTORmTOR signalingsignaling [21] [21] ↑ Cross-sectionalCross-sectional areaarea ofof area of muscle ﬁber muscle fiber ↑ ↑ ↑ ↑Protein ProteinProtein synthesis synthesissynthesis HumanHuman ↑ MuscleMuscleMuscle proteinprotein protein ↑ [23[23][23]] ↑mTOR mTORmTOR signaling signalingsignaling LeucineLeucine Meat,Meat, milk milk / / mTOR signaling Leucine Meat, milk // ↑ ↑↑Protein ProteinProtein synthesis synthesissynthesis C2C12C2C12 cells cells ↑ MuscleMuscle↑ Muscle proteinprotein protein [22[22][22]] ↑↑mTOR mTORmTOR signaling signalingsignaling

↑↑Protein ProteinProtein synthesis synthesissynthesis ValineValine Meat,Meat, milk milk Cachexia Cachexia NMRI NMRI mice mice ↑ MuscleMuscle↑ Muscle weightweight weight [26[26][26]] ↓↓Protein ProteinProtein degradation degradationdegradation

↑↑Protein ProteinProtein synthesis synthesissynthesis IsoleucineIsoleucineIsoleucine Meat,Meat, milk milk /// SDSD SD ratsrats rats ↑ MuscleMuscle↑ Muscle weightweight weight [30[30][30]] ↓↓Protein ProteinProtein degradation degradationdegradation

↑ Branched-chainBranched-chain amino ↑↑mTOR mTORmTOR signaling signalingsignaling /// Meat, Meat, milk milk HindlimbHindlimb suspension suspension SDSDSD ratsrats rats ↑ MuscleMuscle↑ Muscle weightweight weight [28[28,30][28,30],30] aminoacidsacids acids ↓↓MuRF1, MuRF1,MuRF1, MAFbx MAFbxMAFbx

↑ MyoD ↑ ↑↑MyoD MyoDMyoD D-methionineD-methionine SoybeanSoybeanSoybean Cisplatin Cisplatin Wistar Wistar rats rats ↑ MuscleMuscle↑ Muscle weightweight weight [31[31][31]] ↓↓MuRF1, MuRF1,MuRF1, MAFbx MAFbxMAFbx

↑ Breast muscle MethionineMethionine SoybeanSoybeanSoybean /// Broilers Broilers ↑ BreastBreast musclemuscle growthgrowth ↑↑Myf5, Myf5,Myf5, MEF2A MEF2AMEF2A [33 [33] [33]] growth

↑ ↓ TNF-TNF-αα C2C12C2C12 ↑ CellCell↑ Cell differentiationdifferentiation differentiation ↓↓p38 p38p38 MAPK MAPKMAPK singnaling singnalingsingnaling [35 [35] [35]] Glutamine Meat Glutamine Meat FastingFasting C57BL/6 C57BL/6 mice mice ↑ MuscleMuscle↑ Muscle weightweight weight ↑↑mTOR mTORmTOR signaling signalingsignaling [36 [36] [36]]

Reduced mechanical Albino mice ↓ MuscleMuscle injuryinjury ↓ MuRF1,MuRF1, caspasecaspase 3,3, MAFbxMAFbx [39] [39] Taurine Fish, shellfish loadingloading Diquat Piglets ↑ MuscleMuscle proteinprotein ↓ MuRF1,MuRF1, MAFbxMAFbx [40] [40] Nutrients 2021, 13, 1914 7 of 36

Table 1. Cont. Nutrients 2021, 13, x FOR PEER REVIEW 7 of 41 Nutrients Protein/Amino 2021, 13, x FOR PEER REVIEW 7 of 41 Structure Example Source Inducer Model Effect Mechanism Ref Acids/Peptides Reduced mechanical ↓ MuRF1, caspase 3, Albino mice ↓ Muscle injury [39] loading MAFbx ↑ Microtubular, mitochondrial Taurine Fish, shellfish CisplatinDiquat C2C12 Piglets cells ↑ Myotubes↑ Muscle size protein ↓↑MuRF1, Microtubular, MAFbx mitochondrial [40[38]] Cisplatin C2C12 cells ↑ Myotubes size function [38] ↑functionMicrotubular, Cisplatin C2C12 cells ↑ Myotubes size [38] mitochondrial function Denervation Swiss albino mice ↑ Muscle mass ↓ MuRF1, MAFbx [43] Denervation Swiss albino mice ↑ Muscle mass ↓ MuRF1, MAFbx [43] Denervation Swiss albino mice ↑ Muscle mass ↓ MuRF1,↓ Oxidative MAFbx stress, [43] S-allyl cysteine Allium sativum ↓ Oxidative stress, S-allylS-allyl cysteine cysteine AlliumAllium sativum sativum H2O2 C2C12 cells ↑ Myotubes size ↓ Oxidativeinflammation stress, [43] H2O2 C2C12 cells ↑ Myotubes size inflammation [43] H2O2 C2C12 cells ↑ Myotubes size inflammation↓ MuRF1, MAFbx [43] ↓ MuRF1, MAFbx Soybean protein-derived ↓ MuRF1,↑ Autophagy MAFbx signaling Soybean protein-derived / Soybean Burn injury Wistar rats ↑ Muscle protein ↑ Autophagy signaling [44] peptidesSoybean / Soybean Burn injury Wistar rats ↑ Muscle protein ↓ MuRF1, MAFbx [44] peptides ↑↓Autophagy MuRF1, MAFbx signaling protein-derivedPYP1-5 // Pyropia Soybean yezoensis Dexamethasone Burn injury C2C12 Wistar cells rats ↑ Myotube↑ Muscle size protein ↓ MuRF1, MAFbx [44 [45]] PYP1-5 / Pyropia yezoensis Dexamethasone C2C12 cells ↑ Myotube size ↓↓MuRF1, MuRF1, MAFbx MAFbx [45] peptides C2C12 cells ↑ Cell diameter ↓ MuRF1, MAFbx C2C12 cells ↑ Cell diameter ↓ MuRF1, MAFbx PYP1-5 / Pyropia yezoensis Dexamethasone C2C12 cells ↑ Muscle↑ Myotube mass size ↓ MuRF1, MAFbx [45] N-myristoylated Cblin / / Dexamethasone ↑ Muscle mass [46] N-myristoylated Cblin / / Dexamethasone C57BL/6 mice ↑ Muscle fiber cross- ↓ MuRF1, MAFbx [46] C57BL/6C2C12 mice cells ↑ Muscle↑ Cell fiber diameter cross- ↓↓MuRF1, MuRF1, MAFbx MAFbx sectional areas [46] N-myristoylated sectional↑ Muscle areas mass Abbreviation: MAFbx, Muscle atrophy F-box; MAPK, /Mitogen-activated protein kinase; mTOR, Mammalian target of rapamycin; MuRF1, Muscle RING-finger protein-1; Myf5, / Dexamethasone C57BL/6 mice ↑ Muscle fiber ↓ MuRF1, MAFbx Abbreviation:RecombinantCblin myogenicMAFbx, Muscle factor 5; atrophy MyoD, MyogenicF-box; MAPK, differentiation Mitogen-activa antigen;ted SD, protein Sprague kinase; Dawley; mTOR, ↑, Increase Mammalia or promote;n target ↓of, Decreaserapamycin; or inhibit. MuRF1, Muscle RING-finger protein-1; Myf5, Recombinant myogenic factor 5; MyoD, Myogenic differentiation antigen; SD, Sprague Dawley; ↑, Increase or promote;cross-sectional ↓, Decrease or areasinhibit. Abbreviation: MAFbx, Muscle atrophy F-box; MAPK, Mitogen-activated protein kinase; mTOR, Mammalian target of rapamycin; MuRF1, Muscle RING-finger protein-1; Myf5, Recombinant myogenic factor 5; MyoD, Myogenic differentiation antigen; SD, Sprague Dawley; ↑, Increase or promote; ↓, Decrease or inhibit. Nutrients 2021, 13, 1914 8 of 36

3.2. Minerals It is well known that minerals play an important role in muscle metabolism and muscle function (Table2). Calcium and magnesium deﬁciency induces muscle atrophy in Wistar rats [49]. The fourth Korea National Health and Nutrition Examination Survey data showed that daily calcium intake was signiﬁcantly lower (2.7%) in subjects with sarcopenia than in those without (6.3%) and there is a strong inverse association between daily calcium intake and sarcopenia in non-obese, older Korean adults [50]. The Maastricht sarcopenia study, which focuses on the differences in nutrient intake and biochemical nutrient status between sarcopenic and nonsarcopenic older adults, suggests that sarcopenic older adults had a 10–18% lower intake of certain nutrients such as magnesium [51]. A randomized controlled trial showed that magnesium supplementation for 12 weeks in healthy elderly women may improve or delay the age-related decline in muscle physical performance and strength [52].

Table 2. Minerals in the prevention of the muscle atrophy in vitro/vivo.

Example Minerals Structure Inducer Model Effect Mechanism Ref Source ↑ Muscle Magnesium / Egg, meat Aging Human /[52] strength ↑ Muscle mass, Calcium/magnesium strength, and Calcium / Egg, meat Human /[50] deficiency physical performance Selenium Human / / [53] deficiency Selenium / Egg, meat ↑ Ca2+ flux, C57BL/6 ↑ Muscle oxidative Aging [54] mice performance stress tolerance C57BL/6 ↓ Inflammation, ↓ IL-6, TNF-α, Tumor [55] mice muscle atrophy myostatin Abbreviation: IL-6, Interleukin-6; TNF-α, Tumor necrosis factor-α; ↑, Increase or promote; ↓, Decrease or inhibit.

Selenium is an essential trace element for human health and its deficiency is associated with muscle healthy. Chariot and Bignani reported that selenium contributes to the prevention and treatment of muscle disorders, muscle pain, tenderness, muscle fiber atrophy, and physical performance for human in selenium-deficient region [53]. In aged C57BL/6 mice, oral supplementation of selenium significantly augments muscle strength [54]. Besides, supplementation with a combination of fish oil and selenium increase soleus and gastrocnemius muscle mass and reduces IL-6, TNF-α, and myostatin levels in gastrocnemius of tumor-bearing C57BL/6 mice [55].

3.3. Vitamins Vitamins play an important role in the prevention of muscular atrophy by inhibiting oxidative stress and related genes (Table3). A lot of evidence indicated that disturbed redox signaling, due to increased production of ROS and decreased antioxidant capacity, is an important regulator of signaling pathways that control both proteolysis and protein synthesis in skeletal muscle. Vitamin C, a water-soluble vitamin, has the potential for treatment or prevention the treatment of muscle atrophy in mice. Vitamin C deﬁciency causes muscle atrophy in mice, which is associated with high expression of muscle atrophy gene of MAFbx and MuRF1 and overproduction of ROS. The muscle atrophy was restored by 12 weeks of vitamin C supplementation [56]. In male Wistar rats, oral vitamin C administration can attenuate overload-induced skeletal muscle hypertrophy [57]. Dietary Nutrients 2021, 13, 1914 9 of 36

vitamin C supplementation is useful for reducing age-related muscle loss in in middle- and older-aged men and women [58]. Vitamin D deficiency may contribute to the development of muscle atrophy and the possible mechanism is related to the increased expression of MAFbx and protein degradation [59]. Oral administration of vitamin D protects against immobilization-induced muscle atrophy in C57BL/6 mice via vitamin D receptor [60]. Moreover, dietary supplement of vitamin D3 significant enhances Wistar rat soleus muscle mass in dexamethasone-induced muscle atrophy model [61]. Vitamin E has been widely investigated as antioxidant interventions to protect against immobilization-induced hindlimb muscle atrophy in Wistar rats [62]. A double-blind randomized controlled trial reported that oral vitamin D and E supplement preserves muscle mass and strength and enhances quality of life in sarcopenic older adults [63]. It was thought that the combination of vitamin C and vitamin E can efficaciously eliminate water-soluble and fat-soluble free radicals at the same time, preventing free radicals from causing oxidative damage to the cell membrane [64]. Thus, future study is warranted to investigate whether supplementation with a combination of vitamin C and vitamin E may have a more pronounced effect compared with the separate treatment of vitamin C and vitamin E. β-Carotene, a red-colored pigment found in plants and animals, is one of the most abundant provitamin A carotenoid in human diet and tissues. It attenuated muscle atrophy by repressing the expressions of MAFbx, MuRF1, Ubiquitin-specific processing protease 14, and Ubiquitin-specific processing protease 19 in murine C2C12 myotube and mouse soleus muscle [65]. Oral administration of coenzyme Q10 (CoQ10), a vitamin-like substance, improves mitochondrial biogenesis and function in skeletal muscle of Goto–Kakizaki rats [66]. Mito- chondria biogenesis play a critical role in the metabolic and physiological adaptation of skeletal muscle [67]. Similarly, Liu et al. reported that CoQ10 administration ameliorates disuse-induced skeletal muscle atrophy via the activation of mitochondrial biogenesis and the amelioration of oxidative stress in SD rats. In addition, the expression of MuRF-1, MAFbx, and Forkhead box O3 (FoxO3) were reduced by the CoQ10 [68]. Nicotinamide mononucleotide is another potential nutraceutical to combat muscle atrophy. Gomes et al. reported that intraperitoneal injection of 500 mg/kg/day nicotinamide mononucleotide for 7 days could reverse muscle atrophy in aged C57BL/6J mice by decreasing the expression of MAFbx and MuRF1 [69]. Long-term administration of nicotinamide mononucleotide enhances age-associated C57BL/6N mice locomotor activity and enhances mitochondrial respiratory capacity in skeletal muscle [70]. Therefore, these results suggest that vitamins have the therapeutic potential for inhibiting muscle atrophy and inducing muscle hypertrophy. The main mechanism is associated with the inhibition of oxidative stress, the activation of mitochondrial biogenesis, and the suppression the expression of genes related to muscular atrophy. NutrientsNutrients 20212021,, 1313,, xx FORFOR PEERPEER REVIEWREVIEW 10 10 ofof 4141 NutrientsNutrients 20212021,, 1313,, xx FORFOR PEERPEER REVIEWREVIEW 10 10 ofof 4141

Nutrients 2021, 13, 1914 10 of 36

TableTable 3. Vitamins 3. Vitamins in inthe the prevention prevention of ofthe the muscle muscle atrophy atrophy in invitro/vivo. vitro/vivo. TableTableTable 3. 3.3. Vitamins VitaminsVitamins in inin the thethe prevention preventionprevention of ofof th ththee emuscle musclemuscle atrophy atrophyatrophy in inin vitro/vivo. vitro/vivo.vitro/vivo. VitaminsVitamins Structure Example Source Induce Inducerr Model Model Effect Effect MechanismMechanism RefRef VitaminsVitaminsVitamins StructureStructureStructure ExampleExampleExample Source SourceSource InduceInduceInduceInducerr r r ModelModelModel EffectEffectEffect MechanismMechanismMechanism RefRefRef

SenescenceSenescenceSenescence markermarker marker ↑ Physical ↓ MuRF1,↓↓ MuRF1,MuRF1, MAFbx MAFbxMAFbx VitaminVitaminVitamin CC C KiwiKiwi fruit,fruit, lemonslemons SenescenceSenescenceSenescence marker markermarker MiceMiceMice ↑↑ PhysicalPhysical performanceperformance ↓↓ MuRF1, MuRF1,MuRF1, MAFbx MAFbxMAFbx [56[56][56]] VitaminVitaminVitamin C CC KiwiKiwiKiwi fruit, fruit,fruit, lemons lemonslemons protein-30-konckoutprotein-30-konckout MiceMiceMice ↑↑↑ Physical PhysicalPhysicalperformance performance performanceperformance ↓ Oxidative↓↓ Oxidative stress stress [56][56][56] protein-30-konckoutprotein-30-konckoutprotein-30-konckout ↓↓↓ OxidativeOxidative OxidativeOxidative stressstress stressstress

↓ Oxidative↓↓ OxidativeOxidative stress stressstress VitaminVitaminVitamin DD D Milk,Milk, meatmeat ImmobilizationImmobilization Immobilization C57BL/6C57BL/6 C57BL/6 micemice mice ↑↑ ↑ MuscleMuscleMuscle massmass mass ↓↓ Oxidative OxidativeOxidative stress stressstress [60[60][60]] VitaminVitaminVitamin D DD Milk,Milk,Milk, meat meatmeat ImmobilizationImmobilizationImmobilization C57BL/6C57BL/6C57BL/6 mice micemice ↑↑↑ Muscle MuscleMuscle mass massmass ↓ MuRF1,↓↓ MuRF1, MAFbx MAFbx [60][60][60] ↓↓↓ MuRF1,MuRF1, MuRF1,MuRF1, MAFbxMAFbx MAFbxMAFbx

Immobilization Wistar rats / ↓ ↓↓ Oxidative stress [62] ImmobilizationImmobilizationImmobilizationImmobilizationImmobilization WistarWistarWistar Wistar rats ratsrats rats / / / Oxidative↓↓↓ OxidativeOxidative OxidativeOxidative stress stressstress stressstress [62 [62] [62] [62] [62]] VitaminVitamin EE SoybeanSoybean oiloil VitaminVitaminVitaminVitamin E EE E SoybeanSoybeanSoybeanSoybean oil oil oiloil Aging Human ↑ Muscle↑ Musclemass/strength / [63] AgingAgingAgingAging HumanHumanHuman Human ↑↑↑ MuscleMuscle MuscleMuscle mass/strengthmass/strength mass/strengthmass/strength /[// / / 63[63][63][63][63]] Aging Human Musclemass/strength mass/strength / [63] ↓↓ OxidativeOxidative stressstress ↓ Oxidative↓↓ OxidativeOxidative stress stressstress ββ-Carotene-Carotene CarrotCarrot DenervationDenervation ddYddY micemice ↑↑ MuscleMuscle massmass ↓↓ MuRF1,MuRF1, MAFbx,MAFbx, USP14,USP14, [65][65] βββ-Caroteneβ-Carotene-Carotene-Carotene CarrotCarrotCarrotCarrot DenervationDenervationDenervation Denervation ddYddYddYddY mice micemicemice ↑↑↑ Muscle MuscleMuscle mass massmass ↓ MuRF1,↓↓ MuRF1, MuRF1,MuRF1, MAFbx, MAFbx, MAFbx,MAFbx, USP14, USP14, USP14,USP14, [65[65][65][65]] USP19 USP19USP19USP19USP19

↑↑ MitochondriaMitochondriall biogenesisbiogenesis 10 ↑ ↑ ↑ ↑↑ Mitochondria MitochondriaMitochondrial llbiogenesis biogenesisbiogenesis CoenzymeCoenzyme QQ1010 SardineSardine DisuseDisuse SDSD ratsrats ↑ MuscleMuscleMuscle crosscross cross sectionsection Mitochondrial biogenesis [68][68] CoenzymeCoenzyme QQ 1010 SardineSardineSardine DisuseDisuse Disuse SDSD SD ratsrats rats ↑↑ MuscleMuscle crosscross sectionsection ↓↓ MuRF1, MAFbx, FoxO3 [68[68][68]] section ↓ MuRF1,↓↓↓ MuRF1,MuRF1, MuRF1,MuRF1, MAFbx, MAFbx,MAFbx, MAFbx,MAFbx, FoxO3 FoxO3FoxO3 FoxO3FoxO3

NicotinamideNicotinamide ↑↑ MtochondrialMtochondrial oxidativeoxidative NicotinamideNicotinamideNicotinamideNicotinamide Broccoli,Broccoli, avocadoavocado AgingAging C57BL/6NC57BL/6N ↑↑ PhysicalPhysical↑ Physical performanceperformance ↑ Mtochondrial↑↑ Mtochondrial MtochondrialMtochondrial oxidative oxidative oxidativeoxidative [70][70] mononucleotide Broccoli,Broccoli,Broccoli,Broccoli, avocado avocadoavocado AgingAgingAging Aging C57BL/6NC57BL/6NC57BL/6N C57BL/6N ↑↑↑ Physical PhysicalPhysical performance performanceperformance metabolism [70[70][70][70]] mononucleotidemononucleotidemononucleotidemononucleotide performance metabolismmetabolismmetabolismmetabolism

Abbreviation: MAFbx, Muscle atrophy F-box; MuRF1, Muscle RING-finger protein-1; USP 14, Ubiquitin-specific processing protease 14; USP 19, Ubiquitin-specific processing protease Abbreviation:Abbreviation:Abbreviation:Abbreviation: MAFbx, MAFbx, MAFbx, Muscle MuscleMuscle atrophy atrophy atrophyatrophy F-box; F-box; F-box;F-box; MuRF1, MuRF1, MuRF1,MuRF1, Muscle Muscle MuscleMuscle RING-finger RING-fi RING-fiRING-fi protein-1;ngerngernger protein-1; protein-1;protein-1; USP 14, Ubiquitin-specificUSP USPUSP 14, 14,14, Ubiquiti UbiquitiUbiquiti processingn-specificn-specificn-specific protease processing processingprocessing 14; USP protease proteaseprotease 19, Ubiquitin-specific 14; 14;14; USP USPUSP 19, 19,19, Ubiquitin-specific Ubiquitin-specificUbiquitin-specific processing protease processing processing19;processing FoxO3, Forkhead protease proteaseproteasebox 19; FoxO3,↑ Forkhead box O3;↓ ↑↑, Increase or promote; ↓↓, Decrease or inhibit. 19;19;19; O3;FoxO3, FoxO3,FoxO3,, Increase Forkhead ForkheadForkhead or promote; box boxbox O3; O3;O3;, Decrease↑ ↑,↑, ,Increase,Increase IncreaseIncrease or inhibit.oror oror promote;promote; promote;promote; ↓ ↓,↓, ,Decrease,Decrease DecreaseDecrease oror oror inhibit.inhibit. inhibit.inhibit. Nutrients 2021, 13, 1914 11 of 36

3.4. Fatty Acids Growing evidence supports the essential role of fatty acid in the regulation of skeletal muscle mass and function (Table4). For example, docosahexaenoic acid protects mouse C2C12 myoblasts from palmitate-induced atrophy via promoting the expression of peroxisome proliferator-activated receptor γ coactiva-tor-1α (PGC-1α) and attenuating of endoplasmic reticulum stress-associated caspase signaling [71,72]. Woodworth-Hobbs et al. found that docosahexaenoic acid prevents muscle proteolytic induced by palmitate in C2C12 myotubes through the reestablishment of the Akt/FoxO signaling pathway [73]. Similar to docosahexaenoic acid, oleate also prevents palmitate-induced atrophy partly via inhibition of mitochondrial ROS production in C2C12 myotubes [74]. Eicosapentaenoic acid, an omega-3 polyunsaturated fatty acid, has diverse physiological activity including anti-inflammatory and anticachectic actions. Oral administration of eicosapentaenoic acid attenuates arthritis-induced muscle wasting in Wistar rats by decreasing the expression of MAFbx and MuRF1 and increasing the expression of proliferating cell nuclear antigen, MyoD, and myogenin [75]. Dietary supplementation of menhaden fish oil, mainly containing omega-3 unsaturated fatty acids and docosahexaenoic acid, could suppress lipopolysaccharide-induced muscle atrophy in piglets through the modulation of Akt/FoxO, Toll-like receptors and nucleotide-binding oligomerization domain protein signaling pathways [76]. Recently, in another study, dietary menhaden fish oil intake suppresses MuRF1 expression by decreasing TNF-α production in denervation-induced muscle atrophy in C57BL/6J mice [77]. Moreover, a randomized controlled trial suggests that fish oil-derived omega-3 unsaturated fatty acids increase muscle mass and function in healthy older adults [78]. Azelaic acid, a naturally occurring C9 omega-dicarboxylic acid, found in a variety of foods including oatmeal and barley, is a good candidate myogenic molecule that war- rants further investigation. Thach et al. reported that administration of azelaic acid stimulates mitochondrial biogenesis, mitochondrial contents, and autophagy in skeletal muscle tissues via activation of olfactory receptor 544 in HFD-induced obese C57BL/6J mice and C2C12 myotubes. The primary mechanism is associated with cyclic adenosine monophosphate-response element binding PGC-1α-extracellular signal-regulated kinase-1/2 signaling axis [79]. Arachidonic acid (5,8,11,14-eicosatetraenoic acid C20:4, omega-6) supplementation enhances C2C12 myotubes cell growth and development via cyclooxygenase-2-dependent pathway [80]. Royal jelly is rich in multiple fatty acids, such as trans-10-hydroxy-2-decenoic acid and 10-hydroxydecanoic acid. It attenuates denervation-induced skeletal muscle atrophy in C57BL/6J mice and stimulates myoblast proliferation and differentiation of C2C12 cells [81]. Nutrients 2021, 13, x FOR PEER REVIEW 12 of 41 Nutrients NutrientsNutrients 2021 20212021, ,,13 1313, ,,x xx FOR FORFOR PEER PEERPEER REVIEW REVIEWREVIEW 12 12 12 ofofof 414141 Nutrients 2021, 13, x FOR PEER REVIEW 12 of 41 Nutrients 2021, 13, 1914 12 of 36

TableTableTableTable 4. 4.4. 4. Fatty FattyFattyFatty acids acidsacids acids in inin in the thethe the prevention preventionprevention prevention of ofof of the thethethe the muscle musclemusclemuscle muscle atrophy atrophyatrophyatrophy atrophy in ininin in vitro/vivo. vitro/vivo.vitro/vivo.vitro/vivo. vitro/vivo. Table 4. Fatty acids in the prevention of the muscle atrophy in vitro/vivo. Fatty Acids Structure Example Source Inducer Model Effect Mechanism Ref FattyFattyFatty Acids Acids Acids Structure StructureStructure ExampleExample Example Source Source Source InduceInduceInduce Inducerrr r ModelModelModel Model Effect EffectEffect MechanismMechanismMechanismMechanism Ref RefRefRef Fatty Acids Structure Example Source Inducer Model Effect ↑Mechanism PGC-1α, Akt Ref ↑ PGC-1↑↑↑α PGC-1 ,PGC-1PGC-1 Akt ααα,, , Akt AktAkt DocosahexaenoicDocosahexaenoic acid Fish, milk Palmitate C2C12 cells ↑ Cell growth ↓ Endoplasmic↑ PGC-1α, reticulumAkt [71,72] DocosahexaenoicDocosahexaenoicDocosahexaenoic acid acidacid Fish,Fish,Fish, milk milk milk Palmitate Palmitate Palmitate C2C12C2C12C2C12 C2C12 cells cellscells cells ↑↑↑ Cell Cell CellCell growth growth growthgrowth ↓↓↓Endoplasmic↓ Endoplasmic EndoplasmicEndoplasmic reticulum reticulumreticulum [ 71,72[71,72][71,72][71,72]] acid ↑ ↓ stress Docosahexaenoic acid Fish, milk Palmitate C2C12 cells Cell growth reticulum Endoplasmic stressstressstressstress reticulum [71,72] ↓ TNF-stressα, IL6 ↓ TNF-↓↓α↓, TNF- IL6TNF-TNF-ααα,, , IL6 IL6IL6 Oleic acid Sesame Palmitate C2C12 cells ↑ Myotube size ↓↓ Drp1, Fis1 [74] OleicOleicOleic acid acid acid SesameSesameSesame PalmitatePalmitatePalmitate C2C12C2C12C2C12 C2C12 cells cellscells cells ↑↑↑ Myotube Myotube MyotubeMyotube size size sizesize ↓ Drp1,↓↓↓ Fis1 TNF- Drp1, Drp1,Drp1,α Fis1, Fis1 Fis1IL6 [74] [74][74][74] ↑ ↓ ↓ Oleic acid Sesame Palmitate C2C12 cells Myotube size ↓ Myostatin,↓↓↓ Myostatin, Myostatin,Myostatin,Myostatin, MAFbxDrp1, Fis1 MAFbx MAFbxMAFbxMAFbx [74] ↓ Myostatin, MAFbx

↑↑PCNA, PCNA, MyoD, MyoD, myogenin EicosapentaenoicEicosapentaenoic acid Fish, nut Arthritis Wistar rats ↑ Muscle mass ↑↑↑ PCNA, PCNA,PCNA, MyoD, MyoD,MyoD, myogenin myogeninmyogenin [75] EicosapentaenoicEicosapentaenoicEicosapentaenoic acid acidacid Fish,Fish,Fish, nut nut nut Arthritis Arthritis Arthritis WistarWistarWistar Wistar rats ratsrats rats ↑↑↑ Muscle Muscle MuscleMuscle mass mass massmass ↑myogenin PCNA,↓ MuRF1, MyoD, MAFbx myogenin [75] [75][75][75] Eicosapentaenoicacid acid Fish, nut Arthritis Wistar rats ↑ Muscle mass ↓↓↓ MuRF1, MuRF1,MuRF1, MAFbx MAFbxMAFbx [75] ↓ MuRF1,↓ MuRF1, MAFbx MAFbx

Arachidonic acid Pine nut / C2C12 cells ↑↑ Cell growth ↑ ↑ Cyclooxygenase 2 [80] ArachidonicArachidonicArachidonic acid acid acid PinePinePine nut nut nut // / C2C12C2C12C2C12 C2C12 cells cellscells cells ↑↑↑ Cell Cell CellCell growth growth growthgrowth Cyclooxygenase↑↑↑ Cyclooxygenase CyclooxygenaseCyclooxygenase 2 2 22 [80] [80] [80] [80] Arachidonic acid Pine nut / C2C12 cells ↑ Cell growth ↑ Cyclooxygenase 2 [80] HFD C57BL/6J mice ↑↑↑ Muscle function ↑↑↑↑Mitochondrial Mitochondrial biogenesis [79] HFDHFDHFD C57BL/6JC57BL/6JC57BL/6J C57BL/6J mice micemice mice ↑ Muscle Muscle MuscleMuscle function function functionfunction Mitochondrial MitochondrialMitochondrial biogenesis biogenesisbiogenesis [79] [79] [79] [79] Azelaic acid Oatmeal, barley HFD C57BL/6J mice ↑ Muscle function ↑biogenesis MitochondriaMitochondriall biogenesis,biogenesis [79] AzelaicAzelaicAzelaic acid acidacid Oatmeal,Oatmeal,Oatmeal, barley barleybarley / C2C12 cells / ↑↑↑ Mitochondria MitochondriaMitochondriall l biogenesis, biogenesis,biogenesis, [79] AzelaicAzelaic acid acid Oatmeal,Oatmeal, barley barley // / C2C12C2C12C2C12 cells cellscells / / / ↑ Mitochondriaautophagyl biogenesis, [79][79][79] / C2C12 cells / ↑ Mitochondrialautophagyautophagyautophagy [79] Abbreviation:Abbreviation:Abbreviation: Akt, Akt,Akt, protein proteinprotein kinase kinasekinase B; B;B; Drp DrpDrp 1, 1,1, dynamin-related dynamin-relateddynamin-related prot protproteineinein 1; 1;1; Fis1, Fis1,Fis1, Mitochondrial MitochondrialMitochondrial/ Fission FissionFission C2C12 1 111 Protein; Protein;Protein;Protein; cells HFD, HFD,HFD,HFD, high highhighhigh fat fatfatfat die diediedie /t;t;t;t; IL-6, IL-6,IL-6,IL-6, Interleukin-6; Interleukin-6;Interleukin-6;Interleukin-6;biogenesis, MAFbx, MAFbx,MAFbx,MAFbx,autophagy Muscle MuscleMuscleMuscle atrophy atrophyatrophyatrophy [ F-box; 79F-box;F-box;F-box;] MyoD,Abbreviation:MyoD,MyoD, MyogenicMyogenic Myogenic Akt, differentiationdifferentiation differentiation protein kinase antigen;antigen; antigen; B; Drp PCNA PCNAPCNA1, dynamin-related,,, , Proliferating Proliferating ProliferatingProliferating cell protcell cellcell nuclear nuclear einnuclearnuclear 1; Fis1, antigen; antigen; antigen;antigen; Mitochondrial PGC-1 PGC-1 PGC-1PGC-1ααα,,, , Peroxisome Peroxisome Peroxisome PeroxisomeFission 1 Protein; proliferator-activated proliferator-activated proliferator-activatedproliferator-activated HFD, high fat receptor receptor diereceptorreceptort; IL-6, γ γ γ coactiva-tor-1 coactiva-tor-1 Interleukin-6;coactiva-tor-1coactiva-tor-1autophagyα ααMAFbx,;;; ; TNF- TNF- TNF-TNF-ααα, ,, ,Muscle Tumor Tumor TumorTumor necrosis atrophynecrosis necrosisnecrosis factor- factor- F-box;factor-factor- α; ↑, Increase or promote; ↓, Decrease or inhibit. αMyoD,αα;Abbreviation:; ; ↑ ↑↑,, , Increase IncreaseIncrease Myogenic or or Akt,or promote; promote;promote; differentiation protein kinase ↓ ↓↓,, , Decrease DecreaseDecrease B; antigen; Drp 1, or oror dynamin-related inhibit. inhibit. inhibit.PCNA , Proliferating protein 1; cell Fis1, nuclear Mitochondrial antigen; Fission PGC-1 1 Protein;α, Peroxisome HFD, high proliferator-activated fat diet; IL-6, Interleukin-6; receptor MAFbx, γ coactiva-tor-1 Muscle atrophyα F-box;; TNF- MyoD,α, Tumor Myogenic necrosis differentiation factor- α;antigen; ↑, Increase PCNA, or Proliferatingpromote; ↓, cellDecrease nuclear or antigen; inhibit. PGC-1 α, Peroxisome proliferator-activated receptor γ coactiva-tor-1α; TNF-α, Tumor necrosis factor-α; ↑, Increase or promote; ↓, Decrease or inhibit. Nutrients 2021, 13, 1914 13 of 36

4. Phytochemicals Phytochemicals, powerful nutrient-like substances found in fruits, vegetables, and grains, have shown potential muscle-speciﬁc effect in several studies. The results of those studies are reported later separately for different phytochemicals, mainly including polyphenols, ﬂavonoids, polysaccharides, alkaloids, and triterpenoids. Table2 presents selected articles which highlight the role of phytochemicals in the prevention and treatment of muscle atrophy in various models.

4.1. Polyphenols Polyphenols, a large family of naturally occurring organic compounds characterized Nutrients 2021, 13, x FOR PEER REVIEW by multiples of phenol units, contribute to the prevention of muscle atrophy [ 82]. Dietary 14 of 41 Nutrients Nutrients 20212021,, 1313,, xx FORFOR PEERPEER REVIEWREVIEW 14 14 ofof 4141 Nutrients 2021, 13, x FOR PEER REVIEW polyphenols are widely distributed in numerous foods including vegetables, fruits, and 14 of 41 Nutrients 2021, 13, x FOR PEER REVIEW 14 of 41 whole grains [83]. Here, we will summarize the existing scientific evidence gleaned from in vitro and in vivo studies that support the beneficial impacts of dietary polyphenols on the muscle atrophyTable 5. Polyphenols (Table5). in the prevention of the muscle atrophy in vitro/vivo. TableTable 5.5. PolyphenolsPolyphenols inin thethe preventionprevention ofof thethe musclemuscle atrophyatrophy inin vitro/vivo.vitro/vivo. Table 5. Polyphenols in the prevention of the muscle atrophy in vitro/vivo. Polyphenols StructureTable 5. PolyphenolsExampleTable in Source 5. the Polyphenols prevention in ofInduce the the prevention muscler atrophy of the in muscleModel vitro/vivo. atrophy in vitro/vivo.Effect Mechanism Ref PolyphenolsPolyphenols StructureStructure ExampleExample SourceSource InduceInducerr ModelModel EffectEffect MechanismMechanism RefRef Polyphenols Structure Example Source Inducer Model Effect ↓↓ NF-MechanismκB, TNF-α, IL-1β Ref PolyphenolsPolyphenols Structure Structure Example Example Source Source InducerStreptozotocinInducer Model C57BL/6J EffectModel mice Mechanism↑ MuscleEffect weight Ref ↓ NF-NF-MechanismκκB,B, TNF-TNF-αα, , IL-1IL-1ββ Ref[84] Streptozotocin C57BL/6J mice ↑↑ Muscle weight ↓↓ NF-κB, TNF-α, IL-1β [84] Streptozotocin C57BL/6J mice ↑ Muscle weight ↓ MuRF1,MuRF1, MAFbxMAFbx [84] Streptozotocin C57BL/6J mice ↓ NF-κB, TNF-α ,Muscle IL-1β weight ↓ ↓NF- MuRF1,κB, TNF- MAFbxα, IL-1 β [84] Streptozotocin C57BL/6J mice ↑ Muscle weight ↑ [84] ↓ MuRF1, MAFbx CurcuminCurcumin TurmericTurmeric Streptozotocin C57BL/6J mice ↓ MuRF1,↑↑ MAFbx Muscle MuscleMuscle mass massweight andand [84] Curcumin TurmericTurmeric Chronic hypobaric ↑ Muscle mass and ↓ MuRF1, MAFbx CurcuminCurcumin Turmeric Chronic hypobaric ↑ Muscle mass and ↓ Chronic hypobaric ↑ MuscleSD mass rats and improved physical ↓ Muscle proteolysis [85] Chronic hypobaricChronichypoxia hypobaric SDSD ratsrats ↑improvedimproved physicalphysical ↓ MuscleMuscle proteolysisproteolysis [85] [85] Curcumin Turmeric hypoxiaSD rats improved physical ↓ Muscle proteolysis Muscle mass [and85] hypoxiaChronichypoxia hypobaric SD rats improvedperformance physical ↓ Muscle proteolysis [85] hypoxia performanceSD rats improvedperformanceperformance physical ↓ Muscle proteolysis [85] hypoxia performance ↑ Mitochondrial biogenesis ↑ Mitochondrial biogenesis ↑ Mitochondrial biogenesis ↑ Muscle weight, fiber performance ↑ Mitochondrial biogenesis Streptozotocin C57BL/6J mice ↓ MuRF-1, cleaved caspase-3, [86] Streptozotocin C57BL/6Jsize mice ↑ Muscle weight, fiber size ↓↑ MuRF-1, Mitochondrial cleaved biogenesis caspase-3, [86] Streptozotocin C57BL/6J mice ↑↑mitophagy Muscle weight, fiber size ↓↓ MuRF-1, cleaved caspase-3, [86] Streptozotocin C57BL/6J mice ↑ Muscle weight, fiber size ↓↑ MuRF-1, Mitochondrial cleaved biogenesis caspase-3, [86] ResveratrolResveratrol RedRed winewine Streptozotocin C57BL/6J mice Muscle weight, fiber size MuRF-1,mitophagymitophagy cleaved caspase-3, [86] ResveratrolResveratrol RedRed wine wine C26 adenocarcinoma CD2F1 mice ↑ Muscle mass ↑↓ NF-κB, MuRF1 [87] ↓ mitophagy Streptozotocin C57BL/6J mice Muscle↑ weight, fiber size MuRF-1,↓ cleaved caspase-3, [86] Resveratrol Red wine C26C26 adenocarcinomaadenocarcinoma CD2F1CD2F1 micemice ↑ MuscleMuscle massmass ↓ NF-NF-mitophagyκκB,B, MuRF1MuRF1 [87] [87] Resveratrol Red wine C26 adenocarcinoma CD2F1 mice ↑ Muscle mass ↓ NF-mitophagyκB, MuRF1 [87] ↑↑ [88] ↓ ↓ DenervationC26 Denervationadenocarcinoma ICR mice ↑ CD2F1MuscleICR weight mice mice ↓ MAFbx↑ Muscle Muscle weight mass NF-↓ MAFbxκB, MuRF1 [88][87] C26 adenocarcinomaDenervationDenervation CD2F1ICRICR micemice mice ↑↑ MuscleMuscleMuscle weightweightmass ↓ NF-↓ κ MAFbxMAFbxB, MuRF1 [87] [88] [88] Denervation ICR mice ↑ Muscle weight ↓ MAFbx [88] Denervation ICR mice ↑ Muscle weight ↓ MAFbx [88] ↓ ↓ OxidativeOxidative stress,stress, proteolysis,proteolysis, Astaxanthin Shrimp, crab Immobilization Wistar rats ↓ Oxidative stress,↑ proteolysis, Muscle mass ↓ Oxidative stress, proteolysis, [89] AstaxanthinAstaxanthin Shrimp, crab crab Immobilization Immobilization Wistar rats ↑ MuscleWistar mass rats ↑ Muscle mass[89] [89] Astaxanthin Shrimp, crab Immobilization Wistar rats apoptosis,↑ ROS Muscle mass ↓ Oxidativeapoptosis, stress, ROS proteolysis, [89] Astaxanthin Shrimp, crab Immobilization Wistar rats ↑ Muscle mass ↓ Oxidativeapoptosis,apoptosis, stress, ROSROSproteolysis, [89] ↑ apoptosis, ROS Astaxanthin Shrimp, crab Immobilization Wistar rats Muscle mass [89] apoptosis, ROS

Epicatechin Epicatechin gallate GreenGreen tea tea CardiotoxinCardiotoxin C57BL/6 mice ↑C57BL/6Muscle ﬁber size mice ↑ Myf5,↑↑ MyoD Muscle fiber [90size] ↑↑ Myf5, MyoD [90] EpicatechinEpicatechin gallategallategallate GreenGreen teatea CardiotoxinCardiotoxin C57BL/6C57BL/6 micemice ↑ MuscleMuscle fiberfiber sizesize ↑ Myf5,Myf5, MyoDMyoD [90] [90] Epicatechin gallate Green tea Cardiotoxin C57BL/6 mice ↑ Muscle fiber size ↑ Myf5, MyoD [90] Epicatechin gallate Green tea Cardiotoxin C57BL/6 mice ↑ Muscle fiber size ↑ Myf5, MyoD [90]

Nutrients 2021, 13, x FOR PEER REVIEW 15 of 41 ↑ MyoD, SOD ↑ MyoD, SOD Epicatechin Cocoa, green tea Aging ICR mice ↑ Bone mass ↑ [91] ↑↑ MyoD, SOD EpicatechinEpicatechin Cocoa,Cocoa, greengreen teatea AgingAging ICRICR micemice ↓ MuRF1↑ BoneBone massmass MyoD, SOD [91][91] Epicatechin Cocoa, green tea Aging ICR mice ↑ Bone mass ↑ ↓↓MyoD, MuRF1 SOD [91] Epicatechin Cocoa, green tea Aging ICR mice ↑ Bone mass ↑ MyoD,↓ MuRF1MuRF1 SOD [91] Epicatechin Cocoa, green tea Aging ICR mice ↑ Bone mass ↓ MuRF1 [91] ↓ MuRF1

↑ Muscle mass, muscle Epigallocatechin- ↑ IGF-1,↑ Muscle IL-15 mass, muscle ↑ IGF-1, IL-15 Green tea Aging SD rats ﬁber cross-sectional [92] Epigallocatechin-3-gallate3-gallate Green tea Aging SD rats ↓ MuRF1, MAFbx [92] areas fiber cross-sectional areas ↓ MuRF1, MAFbx

↓ Oxidative stress, NF-κB Pomegranate extract / Pomegranate TNF-α C57BL/6 mice ↑ Muscle mass activation, Akt/mTOR [93] signaling Aging/ Human ↑ Muscle founction ↑ Mitochondrial founction [94] Aging/HFD C57BL/6J mice ↑ Muscle founction ↑ Mitochondrial founction [95] Urolithin A Pomegranate / C2C12 cells / ↑ Mitochondrial founction [95]

/ C. elegans ↑ Lifespan, muscle heath ↑ Mitochondrial founction [95] ↓ FoxO1, FoxO3, MAFbx Denervation Mice ↑ Muscle weight [96] MuRF1 Urolithin B Pomegranate / C2C12 cells ↑ Protein synthesis ↑ mTORC1 signaling [96]

Glabridin Licorice Dexamethasone C2C12 cells ↑ Muscle protein ↓ MuRF1 [97]

Flavan 3-ol Cocoa Hindlimb suspension C57BL/6J mice ↑ Muscle mass ↓ MuRF1 [98]

↑ Sirtuin 1 / db/db mice ↑ Muscle fiber size [99] Oligonol / Lychee ↓ MuRF1, MAFbx, FoxO3a Palmitate C2C12 cells ↑ Myotube differentiation ↓ MuRF1, MAFbx [99] Nutrients 2021, 13, x FOR PEER REVIEW 15 of 41 Nutrients 2021, 13, x FOR PEER REVIEW 15 of 41 Nutrients 2021, 13, x FOR PEER REVIEW 15 of 41

Nutrients 2021, 13, 1914 ↑ Muscle mass, muscle14 of 36 ↑ IGF-1, IL-15 Epigallocatechin-3-gallate Green tea Aging SD rats ↑ Muscle mass, muscle ↑ IGF-1, IL-15 [92] Epigallocatechin-3-gallate Green tea Aging SD rats ↑ Muscle mass, muscle ↓ ↑ IGF-1, IL-15 [92] Epigallocatechin-3-gallate Green tea Aging SD rats fiber cross-sectional areas ↓ MuRF1, MAFbx [92] fiber cross-sectional areas ↓ MuRF1, MAFbx

Table 5. Cont.

Polyphenols Structure Example Source Inducer Model Effect Mechanism Ref ↓ Oxidative stress, NF-κB ↓ Oxidative stress, NF-κB ↓ Oxidative stress, NF-κB ↓ Oxidative stress, NF-κB PomegranatePomegranate extract / Pomegranate TNF-α C57BL/6 mice ↑ Muscle mass activation, Akt/mTOR [93] / Pomegranate TNF-α C57BL/6 mice ↑ Muscle mass activation, Akt/mTOR↑ [93] Pomegranate extractextract / Pomegranate TNF-α C57BL/6 mice ↑ Muscle mass activation, Akt/mTOR [93] Pomegranate extract / Pomegranate TNF-α C57BL/6 mice signaling↑ Muscle mass activation,signaling Akt/mTOR [93] signaling Aging/ Human ↑ Muscle founction ↑ Mitochondrial↑ founction [94] ↑ signaling Aging/ Human ↑ Muscle founction ↑ Mitochondrial founction [94] Aging/ Human ↑ Muscle founction ↑ Mitochondrial founction [94] Aging/HFDAging/HFD C57BL/6J mice ↑C57BL/6JMuscle founction mice ↑ Mitochondrial↑ Muscle founction founction [95] ↑ Mitochondrial founction [95] Urolithin A Pomegranate Aging/HFD C57BL/6J mice ↑ Muscle founction ↑ Mitochondrial founction [95] Urolithin A Pomegranate Aging/HFD/ C57BL/6JC2C12 cells mice Muscle / founction ↑ Mitochondrial founction [95] Urolithin A Pomegranate // C2C12 cellsC2C12 / cells ↑ Mitochondrial founction / [95] ↑ Mitochondrial founction [95] Urolithin A Pomegranate / C2C12 cells / ↑ Mitochondrial founction [95] / ↑ Lifespan,C. elegans muscle ↑ Lifespan, muscle heath ↑ Mitochondrial founction [95] / C. elegans ↑ Mitochondrial↑ founction [95] ↑ / C.heath elegans ↑ Lifespan, muscle heath ↑ Mitochondrial founction [95] / C. elegans ↑ Lifespan, muscle heath ↑ Mitochondrial founction [95] ↓ FoxO1, FoxO3, MAFbx Denervation Mice ↑ Muscle weight ↓ FoxO1, FoxO3, MAFbx [96] ↓ FoxO1, FoxO3,↑ MAFbx ↓ FoxO1, FoxO3, MAFbx DenervationDenervation Mice ↑ MuscleMice weight ↑ Muscle weight[96] MuRF1 [96] Denervation Mice MuRF1↑ Muscle weight MuRF1 [96] Urolithin B Pomegranate MuRF1 UrolithinUrolithin B B PomegranatePomegranate Urolithin B Pomegranate / C2C12 cells ↑ Protein synthesis ↑ mTORC1 signaling [96] / C2C12 cells ↑ Protein synthesis ↑ mTORC1 signaling [96] // C2C12 cells ↑ ProteinC2C12 synthesis cells ↑ mTORC1↑ signaling Protein synthesis [96] ↑ mTORC1 signaling [96]

Glabridin Licorice Dexamethasone C2C12 cells ↑ Muscle protein ↓ MuRF1 [97] GlabridinGlabridin LicoriceLicorice DexamethasoneDexamethasone C2C12 cells ↑ MuscleC2C12 protein cells ↓ MuRF1↑ Muscle protein [97] ↓ MuRF1 [97] Glabridin Licorice Dexamethasone C2C12 cells ↑ Muscle protein ↓ MuRF1 [97]

Flavan 3-ol Cocoa HindlimbHindlimb suspension C57BL/6J mice ↑ Muscle mass ↓ MuRF1 [98] Flavan 3-olFlavan 3-ol CocoaCocoa Hindlimb suspensionC57BL/6J mice C57BL/6J↑ Muscle mass mice ↓ MuRF1↑ Muscle mass [98] ↓ MuRF1 [98] Flavan 3-ol Cocoa suspensionHindlimb suspension C57BL/6J mice ↑ Muscle mass ↓ MuRF1 [98]

Nutrients 2021, 13, x FOR PEER REVIEW 16 of 41

↑ Sirtuin 1 ↑ Sirtuin 1 / db/db mice ↑ Muscle fiber size ↑ [99] ↑ Sirtuin 1 Oligonol / Lychee / db/db mice ↓ MuRF1, MAFbx,↑ Muscle FoxO3a fiber size ↑ Sirtuin 1 [99] Oligonol / Lychee / db/db mice ↑ Muscle fiber size ↓ MuRF1, MAFbx, FoxO3a [99] Oligonol / Lychee / db/db↑ Myotube mice Muscle fiber size ↓ MuRF1, MAFbx, FoxO3a [99] Oligonol / Lychee Palmitate C2C12 cells ↓ MuRF1, MAFbx [99] ↓ MuRF1, MAFbx, FoxO3a Oligonol / Lychee differentiation ↑ MuRF1,↓ MAFbx, FoxO3a Palmitate C2C12 cells ↑ Myotube differentiation ↓ MuRF1, MAFbx [99] Palmitate C2C12 cells ↑ Myotube differentiation ↓ MuRF1, MAFbx [99] ↑ Muscle protein ↑ IGF-1 ↑ Muscle protein ↑ IGF-1 Muscle protein IGF-1 MagnololMagnolol MagnoliaMagnolia officinalis officinalisBladder cancerBladder BALB/ccancer mice BALB/c mice [100] [100] ↓ inflammation ↓ MuRF1, MAFbx,↓ FoxO3ainflammation ↓ MuRF1, MAFbx, FoxO3a

↑ Mononuclear ↑ p38 MAPK ↑ p38 MAPK Corylifol A Psoralea corylifolia L. Dexamethasone C2C12 cells [101] Corylifol A Psoralea corylifolia L. Dexamethasone C2C12myotubes cells ↓↑MuRF1, Mononuclear MAFbx myotubes [101] ↓ MuRF1, MAFbx MuRF1, MAFbx Abbreviation:Abbreviation: Akt, protein kinase Akt, protein B; FoxO1, kinase Forkhead B; FoxO1, box Forkhead O1; FoxO box3, O1; Forkhead FoxO3, Forkheadbox O3; IGF-1, box O3; Insulin-like IGF-1, Insulin-like growth growthfactor 1; factor IL-15 1;, Interleukin-15; IL-15, MAFbx, Muscle atrophy F-box; MAPK, Mitogen-activatedInterleukin-15; protein MAFbx,kinase; Muscle mTOR, atrophy Mamma F-box;lian MAPK, target Mitogen-activated of rapamycin; protein MuRF1, kinase; Muscle mTOR, RING-finger Mammalian target protein-1; of rapamycin; Myf5, MuRF1, Recombinant myogenic factor 5; MyoD, Myogenic Muscle RING-ﬁnger protein-1; Myf5, Recombinant myogenic factor 5; MyoD, Myogenic differentiation antigen; NF-κB, Nuclear factor differentiation antigen; NF-κB, Nuclear factor kappa-B; SD, Sprague Dawley; SOD, Superoxide Dismutase; TNF-α, Tumor necrosis factor-α; ↑, Increase or promote; ↓, Decrease or inhibit. kappa-B; SD, Sprague Dawley; SOD, Superoxide Dismutase; TNF-α, Tumor necrosis factor-α; ↑, Increase or promote; ↓, Decrease or inhibit.

Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-hepta-1,6-diene-3,5-dione), a lipophilic polyphenol and bioactive ingredient of turmeric, alleviates muscle atrophy and promotes muscle health under different conditions. For example, in streptozotocin-induced diabetes C57BL/6J mice dietary administration of curcumin ameliorates muscle atrophy by inhibiting the expressions of MAFbx and MuRF1 [84]. At high altitudes, muscle atrophy caused by chronic hypobaric hypoxia results in decreased physical performance. Cur- cumin increases the number of muscle fibers and decreases muscle fibers proteolysis in SD rats under hypobaric hypoxia, leading to enhanced muscle mass and improved physical performance [85]. Resveratrol (3, 5, 40-trihydroxystilbene), a natural antioxidant found mainly in grape skin, and especially red wine, has been shown to inhibit protein degradation and attenuate skeletal muscle fiber atrophy in the different disease model, including cancer, diabetes, and denervation [86,87]. Oral resveratrol treatment alleviates muscle atrophy induced by C26 adenocarcinoma through the inhibition of NF-κB in CD2F1 mice [87]. Resveratrol improves muscle atrophy and enhances grip strength and running distance in streptozotocin-induced diabetic mice, which is associated with a suppression of MuRF-1 and cleaved caspase-3. Besides, it also inhibits mitophagy and increases mitochondrial biogenesis in skeletal mus- Nutrients 2021, 13, 1914 15 of 36

cle of diabetic mice [86]. Moreover, Asami et al. found that dietary resveratrol attenuates muscle atrophy induced by denervation via the downregulation of MAFbx and p62 in institute of cancer research (ICR) mice [88]. Given the reported anti-muscle atrophy effect of resveratrol and the fact that resveratrol acts as a free radical scavenger, it is likely that resveratrol may improve muscle atrophy by removing free radicals in the muscle and reducing muscle oxidative stress; nevertheless, future confirmatory studies are needed. Astaxanthin, a xanthophyll carotenoid, is a natural antioxidant for oxidative damage. Dietary astaxanthin intake attenuates muscle atrophy caused by immobilization in Wistar mice rats by inhibiting oxidative stress and proteolysis via three major proteolytic pathways, including lysosomal proteases, calpains, and the ubiquitin–proteasome system [102]. Recently, Sun et al. demonstrated that astaxanthin prevents muscle atrophy induced by tail suspension in C57BL/6J mice through protecting the functional stability of mitochondria and alleviating mitochondrial oxidative stress and mitochondria-mediated apoptosis [89]. Tea polyphenols, mainly including epigallocatechin-3-gallate, epigallocatechin, epicatechin-3-gallate, epicatechin, gallocatechins, and gallocatechin gallate, have physiological activities such as antioxidant and anti-inflammation, and also have a positive effect in the prevention and treatment of muscle atrophy [103]. Intraperitoneally administration of epicatechin gallate to C57BL/6 mice stimulates muscle satellite cell activation and differentiation, which is necessary for muscle regeneration. Epicatechin gallate also promotes myogenic differentiation in C2C12 cells [90]. Dietary supplementation of epicatechin prevents muscle loss and regulates the quantity and quality of muscle by increasing the expression of MyoD, superoxide dismutase, and catalase in the biceps femoris muscle and decreasing the expression of FoxO3a, myostatin, and MuRF1 in the soleus muscle of ICR mice [91]. In addition, dietary supplementation of epigallocatechin-3-gallate increases the gastrocnemius muscle mass and the cross-sectional area of muscle fibers in aged SD rats by downregulating MuRF1, MAFbx, and myostatin and increasing IGF-1 mRNA expression [92]. Pomegranate is rich in a variety of phenolic compounds and its extract prevents muscle mass loss induced by TNF-α injection in C57BL/6 mice. The mechanism is associated with the inhibition of oxidative stress, NF-κB, and the ubiquitin-proteasome system and the activation of Akt/mTOR signaling [93]. Recently, urolithin A and urolithin B, two novel natural compounds derived from pomegranates, were identified to have preventive effects against muscle trophy. In C. elegans, urolithin A, as an autophagy inducer, extends lifespan and improves muscle heath [95]. Mitochondrial autophagy in aging skeletal muscle plays an important role in promoting muscle health. In both in vitro (C2C12 myoblasts and Mode-K intestinal cells) and in vivo (aging and HFD-fed C57BL/6J mice) models, urolithin A induces mitophagy and improves grip strength and overnight running distance [95]. Moreover, oral administration of urolithin A improves mitochondrial function and promotes muscle health in the elderly [94]. Urolithin B increases C2C12 myotubes protein synthesis by activating mTORC1 signaling. In vivo, urolithin B reduces muscle weight loss induced by denervation and inhibit protein degradation by downregulating the mRNA expression of atrophy-related genes, such as FoxO1, FoxO3a, MAFbx and MuRF1 [96]. Glabridin, a major bioactivity compound in licorice derived from the dried roots and rhizomes of Glycyrrhiza genus plants and used in both foods and traditional herbal medicine, inhibits dexamethasone-induced protein degradation via downregulating the expression of MuRF1 in C2C12 myotubes [97]. Oral administration of licorice flavonoid oil significantly enhances femoral muscle mass in KK-Ay mice and decreases the expression of MuRF1 and MAFbx, which is related to the activation of mTOR, p70S6K, and FoxO3a [104]. Flavan 3-ol fraction, derived from cocoa, enhances muscle atrophy induced by hindlimb suspension in C57BL/6J mice [98]. Oligonol alleviates palmitate-induced senescent pheno- type in C2C12 myotubes and suppresses the expression of MAFbx and MuRF1. Moreover, dietary oligonol supplementation reduces the expression of MAFbx and MuRF1 through upregulating sirtuin-1 and FoxO3a in diabetic db/db mice [99]. Magnolol attenuates skele- Nutrients 2021, 13, 1914 16 of 36

tal muscle atrophy in bladder cancer-bearing BALB/c mice undergoing chemotherapy via suppression of FoxO3a and induction of IGF-1 and subsequent downregulation of MuRF-1 and MAFbx [100]. Corylifol A, a phenolic compound from Psoralea corylifolia L., enhances myogenesis in C2C12 cells via the activation of p38 MAPKs. It also inhibits dexamethasone-induced muscle atrophy in C2C12 cells, which is related to the inhibition of catabolic pathways and the activation of the anabolic pathway [101]. In addition to above mentioned polyphenols, some extracts rich in polyphenols also with good anti-atrophic activity. For example, chestnut flours extracts, characterized by the composition and quantity of various nutrients and specific bioactive components, such as tocopherols, polyphenols, and sphingolipids, inhibit the expression of MAFbx in C2C12 myotubes muscle atrophy induced by dexamethasone [105]. Red bean extract, abundant in phenolic compounds, significantly increase the phosphorylation of FoxO3 and the protein synthesis associated with PI3K/Akt signaling, and suppresses MuRF1 and MAFbx mRNA expression related with the decreased mRNA level of TNF-α and IL-6 induced by immobilization in C57BL/6N mice, suggesting that red bean extract exerts anti-inflammatory effects by reducing pro-inflammatory cytokines [106]. Overall, polyphenols may be an effective therapeutic strategy for inhibiting muscle atrophy and improving muscle mass and strength. The primary mechanism is related to the inhibition of oxidative stress, inflammation, and muscle atrophy related genes and the activation of IGF-1 signaling pathway. Studies have reported that treatment with combined antioxidant compounds seems more effective compared with single application. For example, the protective effect of a tomato extract containing lycopene, phytofluene, and phytoene on UV-induced erythema formation was more pronounced compared with lycopene treatment alone in human [107]. This could be due to the fact that the interaction between structurally different antioxidant compound may provide more comprehensive protection against oxidative stress. As most of the polyphenols act as antioxidants, it is therefore necessary to investigate the efficacy of a combination of different polyphenol compounds in preventing skeletal muscle atrophy in the future.

4.2. Flavonoids Flavonoids, a class of benzo-gamma-pyrone derivatives abundant in foods and plants, are characterized by a flavone ring and exert anti-inflammation and antioxidant properties [108]. According to different structure characteristics, flavonoids can be divided into several subgroups, including flavonols, isoflavones, chalcones, flavanones, flavanes, flavones, flavanols, flavanonols, and anthocyanidis. Their potential biological activities are highly dependent on specific structures. For example, the metabolism, bioavailability, and biological activity of flavonoids depend upon the configuration, total number of hydroxyl groups, and substitution of functional groups about their nuclear structure [109]. In this section, we will review selected articles where 11 flavonoids were involved and highlight their effect and mechanism in the regulation of muscle atrophy (Table6). Nutrients 2021,, 13,, xx FORFOR PEERPEER REVIEWREVIEW 20 20 ofof 4141 Nutrients Nutrients 20212021, 13,, 13x FOR, 1914 PEER REVIEW 20 of17 41 of 36

Table 6. Flavonoids in the prevention of the muscle atrophy in vitro/vivo. Table 6. Flavonoids in the prevention of thethe musclemuscle atrophyatrophy inin vitro/vivo.vitro/vivo. Flavonoids Structure ExampleTable Source6. Flavonoids in the Inducer prevention of the muscle Model atrophy in vitro/vivo. Effect Mechanism Ref Flavonoids Structure Example Source InduceInducerr Model Effect Mechanism Ref Flavonoids Structure Example Source Inducer Model Effect Mechanism Ref HFDHFD C57BL/6 C57BL/6 mice mice ↑ ExerciseExercise↑ Exercise capacitycapacity capacity ↓↓ MuRF1,MuRF1, MAFbxMAFbx [110] [110] [110 ] HFD C57BL/6 mice ↑ Exercise capacity ↓ MuRF1, MAFbx [110] Parsley,Parsley, celery, celery, and and ApigeninApigenin Parsley, celery, and Apigenin Parsley,grapefrui celery, and ↑ Apigenin grapefrui Palmitic acid C2C12 cells / ↑ MitochondrialMitochondrial contentcontent [110] [110] grapefrui Palmitic acid C2C12 cells / ↑↑ Mitochondrial content [110] Palmitic acid C2C12 cells / Mitochondrial content [110]

↑ MuscleMuscle↑ mass,mass,Muscle musclemuscle mass, ↓↓ Nrf2,Nrf2,Nrf2, NF-NF- κκB,B, TNF- TNF-αα Quercetin Onions HFD C57BL/6J mice [111] QuercetinQuercetin OnionsOnions HFD HFD C57BL/6J C57BL/6J mice mice↑ Muscle mass, muscle ↓↓ Nrf2, NF-κB, TNF-α [111][111][111 ] Quercetin Onions HFD C57BL/6J mice fiberfibermuscle sizesize ﬁber size ↓↓ MuRF1,MuRF1, MAFbxMAFbx [111] fiber size ↓ MuRF1, MAFbx

↑ MyotubeMyotube diameter,diameter, Rattan tea ↑ ↑ Muscle strength, ↑ MyotubeMyotubeMyotube diameter,diameter, diameter, AmpelopsinAmpelopsin Rattan tea (Ampelopsis D-galactoseD-galactose ↑ MuscleMuscle strength,strength, fiberfiber ↑ Myotube diameter, Ampelopsin Rattan (teaAmpelopsis (Ampelopsis D-galactose SD ratsSD rats ↑ Muscleﬁber strength, cross-sectional fiber mitochondrialmitochondrial content, content, Tfam, [112][112][112 ] (dihydromyricetin)(dihydromyricetin)(dihydromyricetin) grossedentata)) /Dexamethasone/Dexamethasone/Dexamethasone SD rats cross-sectional area mitochondrial content, Tfam, [112] (dihydromyricetin) grossedentatagrossedentata) ) /Dexamethasone cross-sectionalarea area Tfam,PGC-1 PGC-1α α PGC-1α

↑ Muscle mass, ↑ MuscleMuscle mass,mass, mitochondrialmitochondrial 5,7- BlackBlack ginger ginger ↑ Muscle mass, ↑ mitochondrial content, 5,7-Dimethoxyflavone AgingAging C57BL/6 C57BL/6 mice mice↑ MuscleMuscle mass,mass, strengthstrength Musclecontent, mass, Tfam, mitochondrial PGC-1α [113][113][113 ] Dimethoxyﬂavone ((Kaempferia(KaempferiaBlack ginger parviflora parviﬂora )) ) strength Tfam, PGC-1α 5,7-Dimethoxyflavone Aging C57BL/6 mice ↑ Muscle mass, strength content,↓ MuRF1,MuRF1, Tfam, MAFbxMAFbx PGC-1 α [113] (Kaempferia parviflora) ↓ MuRF1,MuRF1, MAFbxMAFbx ↓ MuRF1, MAFbx

↑↑ MuscleMuscle function,function, ↑ MuscleMuscle function,function, ↑ MuscleMuscle↑ Muscle functionfunction function andand ↑ Muscle function, // / mdx micemdx mice ↑ morphologymorphology [114][114][114 ] Genistein Soybean Musclemorphologyand function morphology and Genistein Soybean / mdx mice ↓↓ NF-NF-morphologyκκB,B, TNF- TNF- αα [114] GenisteinGenistein SoybeanSoybean morphology NF-NF-κB, TNF-α ↓ NF-κB, TNF-α DenervationDenervation C57BL6/J C57BL6/J mice mice ↑ MuscleMuscle↑ Muscle strengthstrength strength ↓↓ MuRF1,MuRF1, MAFbxMAFbx [115] [115] [115 ] Denervation C57BL6/J mice ↑ Muscle strength ↓ MuRF1, MAFbx [115] ↑ MitochondrialMitochondrial cytochromecytochrome Isoflavin-β / Soybean Thyrotoxicosis Wistar rats ↑ Muscle mass Mitochondrial cytochrome [116] Isoflavin-Isoflavin-β // Soybean Thyrotoxicosis Wistar rats ↑ MuscleMuscle massmass ↑ Mitochondrial↑ cytochrome [116][116] Isoflavin-β / Soybean Thyrotoxicosis Wistar rats ↑ Muscle mass oxidaseMitochondrial activity [116] Isoﬂavin-β / Soybean Thyrotoxicosis Wistar rats ↑ Muscle mass cytochromeoxidase activity oxidase [116] activity ↑ NFATc3,NFATc3, miR-23amiR-23a Delphinidin Blueberry Disuse C57BL/6J mice ↑ MuscleMuscle weightweight [117,118] Delphinidin Blueberry Disuse C57BL/6J mice MuscleMuscle weightweight ↑ NFATc3,↓ miR-23a [117,118][117,118] Delphinidin Blueberry Disuse C57BL/6J mice ↑ Muscle weight ↓ MuRF1MuRF1 [117,118] ↓ MuRF1

Nutrients 2021, 13, x FOR PEER REVIEW 20 of 41

Table 6. Flavonoids in the prevention of the muscle atrophy in vitro/vivo.

Flavonoids Structure Example Source Inducer Model Effect Mechanism Ref HFD C57BL/6 mice ↑ Exercise capacity ↓ MuRF1, MAFbx [110] Parsley, celery, and Apigenin grapefrui Palmitic acid C2C12 cells / ↑ Mitochondrial content [110]

↑ Muscle mass, muscle ↓ Nrf2, NF-κB, TNF-α Quercetin Onions HFD C57BL/6J mice [111] fiber size ↓ MuRF1, MAFbx

↑ Myotube diameter, Ampelopsin Rattan tea (Ampelopsis D-galactose ↑ Muscle strength, fiber SD rats mitochondrial content, Tfam, [112] (dihydromyricetin) grossedentata) /Dexamethasone cross-sectional area PGC-1α

↑ Muscle mass, mitochondrial Black ginger 5,7-Dimethoxyflavone Aging C57BL/6 mice ↑ Muscle mass, strength content, Tfam, PGC-1α [113] (Kaempferia parviflora) ↓ MuRF1, MAFbx

Nutrients 2021, 13, 1914 ↑ Muscle function, 18 of 36 ↑ Muscle function and / mdx mice morphology [114] Genistein Soybean morphology ↓ NF-κB, TNF-α Denervation C57BL6/J mice ↑ Muscle strength ↓ MuRF1, MAFbx [115] Table 6. Cont. ↑ Mitochondrial cytochrome Isoflavin-β / Soybean Thyrotoxicosis Wistar rats ↑ Muscle mass [116] Flavonoids Structure Example Source Inducer Model Effectoxidase Mechanism activity Ref

NutrientsNutrients 20212021,, 1313,, xx FORFOR PEERPEER REVIEWREVIEW ↑↑ NFATc3,NFATc3, miR-23a 21 21 ofof 4141 NutrientsDelphinidin 2021, 13, x FOR PEER REVIEW Blueberry Disuse C57BL/6J mice ↑ Muscle↑ weight [117,118] 21 of 41 Nutrients 2021Delphinidin, 13, x FOR PEER REVIEW Blueberry Disuse C57BL/6J mice Muscle weight ↓ [117 21, 118of ]41 ↓ MuRF1MuRF1

HopHop ((HumulusHumulus HopHop (Humulus (Humulus ↑↑ ↑↑ 8-Prenylnaringenin8-Prenylnaringenin8-Prenylnaringenin Hop (Humulus DenervationDenervationDenervation C57BL/6C57BL/6 C57BL/6 micemice mice ↑ MuscleMuscle↑ Muscle weightweight weight ↑↑ Akt,Akt, IGF-1 IGF-1 [119] [119] [119 ] 8-Prenylnaringenin lupuluslupuluslupulus)) ) Denervation C57BL/6 mice ↑ Muscle weight ↑ Akt, IGF-1 [119] lupulus)

MilkMilk thistlethistle ((SilybumSilybum MilkMilk thistle thistle (Silybum (Silybum ↑↑ ↓↓ SilibininSilibininSilibinin Milk thistle (Silybum PancreaticPancreaticPancreatic cancercancer cancer NCr-nu/nuNCr-nu/nu NCr-nu/nu micemice mice ↑ MuscleMuscle↑ Muscle strengthstrength strength ↓↓ MuRF1,MuRF1, MAFbx MAFbx [120] [120] [120 ] Silibinin marianummarianummarianum)) ) Pancreatic cancer NCr-nu/nu mice ↑ Muscle strength ↓ MuRF1, MAFbx [120] marianum)

↑ ↑↑↑ cAMPcAMP HFDHFD C57BL/6NC57BL/6N ↑↑ MuscleMuscle weight/strengthweight/strengthMuscle ↑ cAMP [121][121] HFDHFD C57BL/6N C57BL/6N ↑ Muscle weight/strength ↓↓ ↑ cAMP [121][121] HFD C57BL/6N ↑ Muscleweight/strength weight/strength ↓↓ MuRF1,MuRF1, MAFbx MAFbx [121] Violets,Violets,Violets, blackberries,blackberries, blackberries, ↓ MuRF1, MAFbx ααα-Ionone-Ionone-Ionone Violets, blackberries, α-Ionone plumsplumsplums ↑↑↑ cAMP,cAMP, MyoD, MyoD, Myogenin Myogenin plums PalmiticPalmiticPalmitic acidacid acid C2C12C2C12 C2C12 cellscells cells ↑↑ MyotubeMyotube↑ Myotube sizesize size ↑ cAMP, MyoD, Myogenin [121][121][121 ] plums Palmitic acid C2C12 cells ↑ Myotube size cAMP,↓↓↓ MuRF1,MuRF1, MyoD, MAFbxMAFbx Myogenin [121] Palmitic acid C2C12 cells ↑ Myotube size ↓ MuRF1, MAFbx [121] ↓ MuRF1, MAFbx ↓↓ MuRF1,MuRF1, MAFbxMAFbx BALB/cBALB/c micemice ↑↑ MuscleMuscle massmass ↓ MuRF1, MAFbx [122][122] BALB/c mice ↑ Muscle mass ↓↓↓ STAT3MuRF1,STAT3 signalingsignaling MAFbx [122] BALB/cBALB/c mice mice ↑ Muscle↑ Muscle mass mass ↓ STAT3 signaling [122][122] CryptotanshinoneCryptotanshinone DanshenDanshen CT26CT26 coloncolonCT26 carcinomacarcinoma colon ↓↓ STAT3 signaling CryptotanshinoneCryptotanshinone DanshenDanshen CT26 colon carcinoma Cryptotanshinone Danshen CT26 coloncarcinoma carcinoma C2C12C2C12 cellscells / / ↓↓ MuRF1,MuRF1, MAFbxMAFbx [122] [122] C2C12 cells / ↓ MuRF1, MAFbx [122] C2C12C2C12 cells cells / / ↓↓ MuRF1, MAFbx [122] [122]

Abbreviation:Abbreviation: Akt,Akt, ProteinProtein kinasekinase B;B; cAMP,cAMP, CyclicCyclic adenosineadenosine monomonophosphate;phosphate; HFD,HFD, HighHigh fatfat diet;diet; IGF-1,IGF-1, Insulin-likeInsulin-like growthgrowth factofactorr 1;1; MAFbx,MAFbx, MuscleMuscle atrophyatrophy F-box;F-box; MuRF1,MuRF1, MuscleMuscle Abbreviation:Abbreviation: Akt, Akt, Protein Protein kinasekinase B; B; cAMP, cAMP, Cyclic Cyclic adenosine adenosine monophosphate; monophosphate; HFD, High HFD, fat High diet; IGF-1,fat diet; Insulin-like IGF-1, Insulin-like growth factor growth 1; MAFbx, facto Muscler 1; MAFbx, atrophy Muscle F-box; MuRF1, atrophy Muscle F-box; RING-ﬁnger MuRF1, Muscle protein-1; RING-fingerAbbreviation:RING-finger protein-1;protein-1; Akt, Protein MyoD,MyoD, kinase MyogenicMyogenic B; cAMP, differentiationdifferentiation Cyclic adenosine antigen;antigen; mono Nrf2,Nrf2,phosphate; NuclNuclearear HFD, factorfactor High erythroid-2erythroid-2 fat diet; IGF-1, relatedrelated Insulin-like factor;factor; NF-NF- growthκκB,B, NuclearNuclear factor factor factor1; MAFbx, kappa-B;kappa-B; Muscle PGC-1PGC-1 atrophyαα,, PeroxisomePeroxisome F-box; MuRF1, proliferator-proliferator- Muscle RING-fingerMyoD, Myogenic protein-1; differentiation MyoD, Myogenic antigen; Nrf2, differentiation Nuclear factor antigen; erythroid-2 Nrf2, related Nucl factor;ear factor NF-κB, erythroid-2 Nuclear factor related kappa-B; factor; PGC-1 NF-α, PeroxisomeκB, Nuclear proliferator-activated factor kappa-B; PGC-1 receptorα,γ Peroxisomecoactiva-tor-1 proliferator-α; STAT3, Signal activatedactivatedtransducer receptorreceptor and activator γγ coactiva-tor-1coactiva-tor-1 of transcriptionαα;; STAT3,STAT3, 3; TNF- SignalSignalα, Tumor transducertransducer necrosis factor- andand acacα;tivatortivator↑, Increase ofof transcriptiontranscription or promote; ↓, 3; Decrease3; TNF-TNF-αα or,, TumorTumor inhibit. necrosisnecrosis factor-factor-αα;; ↑↑,, IncreaseIncrease oror promote;promote; ↓↓,, DecreaseDecrease oror inhibit.inhibit. activated receptor γ coactiva-tor-1α; STAT3, Signal transducer and activator of transcription 3; TNF-α, Tumor necrosis factor-α; ↑, Increase or promote; ↓, Decrease or inhibit. Nutrients 2021, 13, 1914 19 of 36

Apigenin (40,5,7-Trihydroxyflavone) is a flavonoid found in edible plants including parsley, celery, and grapefruit. Choi et al. reported that dietary supplementation of apigenin ameliorates the obesity-induced skeletal muscle atrophy and increases the exercise capacity. The positive effect of apigenin is related to the upregulation of mitochondrial content and downregulation of gene expression of MuRF1 and MAFbx in skeletal muscle of C57BL/6 mice [110]. The group also reported that in C2C12 myotubes, apigenin suppresses muscle atrophy and mitochondrial dysfunction induced by palmitic acid [110]. Dietary supplementation with quercetin (3,30,40,5,7-pentahydroxyflavone), a natural flavonoid mainly present in apples, buckwheat, onions, and citrus fruits, protects against HFD-induced skeletal muscle inflammation and atrophy in C57BL/6 mice by inhibiting the expression of TNF-α, monocyte chemoattractant protein 1, MAFbx, and MuRF1 [123]. Kim et al. reported that quercetin suppresses the expression of atrophic factors including MAFbx and MuRF1 induced by TNF-α injection under obese conditions in C57BL/6 mice. Furthermore, quercetin enhances heme oxygenase-1 protein level by the activation of nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the inhibition of NF-κB in myotubes [111]. Taken together, quercetin may be used as an outstanding dietary supplement to protect against obesity-induced skeletal muscle atrophy. It is reported that quercetin could counteract the HFD-induced obesity in C57BL/6J mice [123]. Obesity is well known to contribute to skeletal muscle atrophy or sarcopenia. Therefore, it is interesting to investigate whether the anti-muscle atrophy effects of quercetin is related to its anti-obesity effect. Ampelopsin, a natural flavonoid from Rattan tea, also called dihydromyricetin, has a variety of physiological activities including anti-atrophy effects. Oral administration of ampelopsin improves the d-galactose-induced muscle atrophy in SD rats owing to the decreased MuRF1 and MAFbx and activated adenosine 50-monophosphate-activated protein kinase (AMPK) and sirtuin-1 signaling pathways [112]. Moreover, ampelopsin administered for 14 days significantly attenuates dexamethasone-induced muscle atrophy in SD rats by reversing mitochondrial dysfunction, which was partially mediated by the PGC-1α/mitochondrial transcription factor A (Tfam) and PGC-1α/mitofusin-2 signaling pathway [124]. 5,7-Dimethoxyflavone, a major bioactive component in Kaempferia parviflora, has the pharmacologic effects on skeletal muscle atrophy. Kim and Hwang reported that oral administration of 5,7-dimethoxyflavone improves the exercise capacity and muscle mass by reducing the mRNA expression of MuRF1 and MAFbx in gastrocnemius muscle of eighteen-month-old C57BL/6J mice. 5,7-Dimethoxyflavone also increases mitochondrial DNA content through upregulating PGC-1α, nuclear respiratory factor 1, and Tfam in soleus muscle [113]. Intraperitoneal injections of genistein, a soy isoflavone, ameliorates muscle function and morphology in mdx mice through inhibiting oxidative stress and blunting proinflammatory factors, such as NF-κB, TNF-α, and MAPKs [114]. Whereafter, Aoyama et al. found that dietary genistein supplementation attenuates denervation-induced muscle atrophy in male C57BL/6J mice [115]. Daily intraperitoneal injections of isoflavin-β, a mixture of isoflavones, prevents thyrotoxicosis-induced muscle mass loss in Wistar rats through increasing muscle total antioxidant capacity and decreasing mitochondrial cytochrome oxidase activity [116]. Moreover, there are also many flavonoids that have been shown to prevent and treat muscular atrophy. For instance, oral administration of delphinidin prevents disuse muscle atrophy by inducing the miR-23a expression and nuclear factor of activated T cells 3 and suppressing MuRF1 expression in skeletal muscle of C57BL/6J mice [117,118]. Dietary ingestion of 8-prenylnaringenin prevents denervation-induced muscle atrophy in C57BL/6 mice by stimulating the phosphorylation of protein kinase B and downregulating MAFbx [119]. Shukla et al. provided compelling evidence that silibinin increases the protein content and decreases MuRF1 and MAFbx expression in skeletal muscle of pancreatic cancer NCr-nu/nu mice [120]. Dietary supplementation of α-ionone, a naturally occurring flavoring agent in violets and blackberries, improves the loss of skeletal muscle induced by HFD in C57BL/6N mice and prevents C2C12 myotubes from palmitic acid-induced atrophy via cyclic adenosine monophosphate signaling [121]. Cryptotanshinone, a major Nutrients 2021, 13, 1914 20 of 36

lipophilic compound found in the root of Danshen, protects against muscle atrophy induced by colon adenocarcinoma CT26 in BALB/c mice and improves myotube atrophy of C2C12 cells, which is associated with the reduced the expression of MuRF1 and MAFbx [122].

4.3. Polysaccharides Polysaccharides, the long chain polymeric carbohydrates composed of monosaccha- ride units bound together by glycosidic linkages, are mainly derived from various plants, fungal and algal sources [125]. Recently, some bioactive polysaccharides have been shown to play an important role in ﬁghting muscle atrophy (Table7). For example, Astragalus polysaccharide, an important bioactive component of Astragalus membranaceus Bunge (Legu-

Nutrients 2021, 13, x FOR PEER REVIEW minosae), inhibits dexamethasone-induced muscle atrophy by increasing phosphorylation 24 of 41 of Akt, mTOR, P70S6K, and rpS6, and FoxO3a in C2C12 myoblasts. Besides, Astragalus polysaccharides also promote cell proliferation and inhibit cell apoptosis in H2O2-induced cell damage in C2C12 cells [126]. Table 7. Polysaccharides in the prevention of the muscle atrophy in vitro/vivo. Polysaccharides StructureTable 7. PolysaccharidesExample Source in theInduce preventionr of the muscleModel atrophy in vitro/vivo.Effect Mechanism Ref Astragalus Astragalus polysaccharide / Dexamethasone C2C12 cells ↑ Myotube diameter ↑ Akt, mTOR, p70S6K, rpS6 [126] Polysaccharides Structuremembranaceus Example Source Bunge Inducer Model Effect Mechanism Ref Astragalus Astragalus ↑ Calf thickness, calf / Dexamethasone C2C12 cells ↑ Myotube diameter ↑ Akt, mTOR, p70S6K,↑ rpS6 AkT, PI3K [126 ] Extracellularpolysaccharide membranaceusAureobasidium Bunge muscle strength, / Dexamethasone ICR mice ↑ Calf thickness, calf muscle ↑ AkT,↓ MAFbx, PI3K MuRF1, myostatin, [127] polysaccharidesExtracellular Aureobasidiumpullulans gastrocnemius muscle / Dexamethasone ICR mice strength, gastrocnemius muscle ↓ MAFbx, MuRF1, myostatin, [127] polysaccharides pullulans sirtuin 1 thicknessthickness and weight and weight sirtuin 1

↓ Inflammation ↓ Inﬂammation Cancer cachexia, cachexia, ↑ Body weight, muscle FucoidanFucoidan BrownBrown algae algae BALB/cBALB/c mice mice↑ Body weight, muscle weight ↓ FoxO3, MuRF1,↓ FoxO3, MAFbx MuRF1,[128 MAFbx] [128] chemotherapychemotherapy weight ↑ IGF-1 signaling↑ IGF-1 signaling

Abbreviation:Abbreviation: Akt, protein Akt,kinase protein B; FoxO3, kinase Forkhead B; FoxO3, box O3; Forkhead IGF-1, Insulin-like box O3; IGF-1, growth Insulin-like factor 1; MAFbx, growth Muscle factor atrophy 1; MAFbx, F-box; Muscle mTOR, atrophy Mammalian F-box; target mTOR, of rapamycin; MuRF1, Muscle RING-fingerMammalian protein-1; target p70S6K, of rapamycin; Ribosomal MuRF1, protein MuscleS6 kinase RING-ﬁnger; PI3K, Phosphoinositide protein-1; p70S6K,3-kinase; rpS6, Ribosomal Ribosomal protein protein S6 kinase;S6; ↑, Increase PI3K, or Phosphoinositide promote; ↓, Decrease or inhibit. 3-kinase; rpS6, Ribosomal protein S6; ↑, Increase or promote; ↓, Decrease or inhibit.

Oral administration of Aureobasidium pullulans polysaccharides ameliorates dexamethasone-induced muscle atrophy in ICR mice. The underlying mechanisms involve the increased expression of genes related to muscle protein synthesis (Akt and PI3K) and the inhibition of genes involved in muscle protein degradation (MAFbx, MuRF1, myostatin, and sirtuin-1) [127]. Dioscorea nipponica extracts is abundant in polysaccharides and protects against injury- induced muscle atrophy by suppressing NF-κB expression in C57BL/6 mice. In vitro model of C2C12 cells, Dioscorea nipponica extracts inhibits TNF-α-induced atrophy and promotes myoblast differentiation [129]. Due to the special growth environment, the polysaccharides extracted from marine sources also have biological activities to prevent muscular atrophy. For example, fucoidan, a kind of fucose-enriched sulphated polysaccharides isolated from brown algae, has recently drawn considerable attention owing to against muscle atrophy. Chen et al. reported that dietary supplement of fucoidan can prevent cancer cachexia-associated muscle atrophy in BALB/c mice during chemotherapy, which may be associated with suppressed muscle wasting-related genes including FoxO3a, MuRF1, and MAFbx and enhanced IGF-1- dependent protein synthesis [128]. Oral administration of fucoidan for 4 weeks improves cross-sectional area of extensor digitorum longus ﬁbers and soleus ﬁbers and enhances the expression of MHC in gastrocnemius muscles muscle in C57BL/6 mice [130].

4.4. Alkaloids Alkaloids, a class of structurally diverse array of natural products, have important biological functions on humans and animal. Nine compounds were collected in the literature: matrine, isoquinoline alkaloids, magnoﬂorine, canadine, tetrahydropalmatine, tomatidine, conessine, theophylline, and apocynin, which are abundant in various plants and show positive physiological effect on muscle atrophy (Table8). Nutrients 2021, 13, x FOR PEER REVIEW 26 of 41 Nutrients 2021, 13, 1914 21 of 36

Nutrients 2021, 13, x FOR PEER REVIEW 26 of 41

Table 8. Alkaloids in the prevention of the muscle atrophy in vitro/vivo. Table 8. Alkaloids in the prevention of the muscle atrophy in vitro/vivo. Alkaloids Structure Example Source Inducer Model Effect Mechanism Ref Alkaloids Structure Example Source Inducer Model Effect Mechanism Ref Table 8. Alkaloids in the prevention of the muscle atrophy in vitro/vivo. Table 8. Alkaloids in the prevention of the muscle atrophy ↑in Musclevitro/vivo.↑ fiberMuscle size, fiber muscle size, CachexiaCachexia Mice Mice ↓↓ MuRF1, MAFbx [ [131]131] muscle mass Alkaloids Structure Example Source Inducer Model Effectmass Mechanism Ref ↑ Muscle fiber size, muscle MatrineMatrine SophoraSophora flavescens flavescens ↑ Muscle fiber size, muscle ↓ Cachexia Mice ↑ ↓Akt/mTOR/p-FoxO3a MuRF1, MAFbx [131] Dexamethasone C2C12 cells ↓ Apoptosismass ↑ Akt/mTOR/p-FoxO3a [131] Dexamethasone C2C12 cells ↓ Apoptosis ↓ [131] ↓ MuRF1, MAFbx Matrine Sophora flavescens ↑ Akt/mTOR/p-FoxO3a Isoquinoline alkaloids / Coptis japonica Dexamethasone/ C2C12 cells ↑ Myoblast↓ Apoptosis differentiation ↑ p38/MAPK, Akt [131] [132] Isoquinoline ↑ Myoblast ↓ MuRF1, MAFbx / Coptis japonica / C2C12 cells ↑↑ p38/MAPK, Akt Akt [132] alkaloids CT26 colon carcinoma C2C12 cells ↑ Myoblastdifferentiation differentiation [132,133] ↓ Isoquinoline alkaloids / Coptis japonica / C2C12 cells ↑ Myoblast differentiation ↑ p38/MAPK,MuRF1, MAFbx Akt [132] CT26 colon ↑ Myoblast ↑↑ p38/MAPK, Akt Akt Magnoflorine Coptis japonica CT26 colon carcinoma C2C12C2C12 cells cells↑ Myoblast differentiation [[132,133]132,133] carcinoma differentiation ↓↓ MuRF1,MuRF1, MAFbx MAFbx Streptozotocin Wistar rats ↑ Muscle mass ↓ MAFbx,MuRF1, MuRF-1MAFbx [133] Magnoflorine Coptis japonica Magnoflorine Coptis japonica ↑ ↓ StreptozotocinStreptozotocin Wistar Wistar rats rats ↑ Muscle↑ Muscle mass mass ↓↓ MAFbx,MAFbx, MuRF-1 MuRF-1 [[133] 133]

↑ p38/MAPK, Akt signaling Canadine Corydalis turtschaninovii CT26 colon carcinoma C2C12 cells ↑ Myoblast Differentiation [134] ↓ MAFbx, MuRF1 ↑ p38/MAPK, Akt CT26 colon ↑ Myoblast ↑ p38/MAPK, Akt signaling CanadineCanadine CorydalisCorydalis turtschaninovii turtschaninovii CT26 colon carcinoma C2C12C2C12 cells cells↑ Myoblast Differentiation signaling [[134]134] carcinoma Differentiation ↓ MAFbx, MuRF1 ↓ MAFbx, MuRF1

Tetrahydropalmatine Corydalis turtschaninovii / C2C12 cells ↑ Myoblast Differentiation ↑ p38/MAPK, Akt signaling [135]

↑ Myoblast ↑ p38/MAPK, Akt TetrahydropalmatineTetrahydropalmatine CorydalisCorydalis turtschaninovii turtschaninovii / /C2C12 C2C12 cells cells↑ Myoblast Differentiation ↑ p38/MAPK, Akt signaling [ [135]135] Tetrahydropalmatine Corydalis turtschaninovii / C2C12 cells MyoblastDifferentiation Differentiation p38/MAPK,signaling Akt signaling [135] Aging C57BL/6 mice ↑ Muscle mass ↑ mTOR signaling [136] Human skeletal Aging/ myotubes,C57BL/6 miceC2C12 ↑↑ MyotubeMuscle mass size ↑ mTOR signaling [136] Tomatidine Tomatoes Aging C57BL/6 mice ↑ Muscle mass ↑ mTOR signaling [136] Humancells skeletal ↑ ↑ Nrf2↑ signaling, mitophagy / myotubes, C2C12 ↑↑ Myotube size ↑ mTOR signaling [136] Tomatidine Tomatoes Aging C. elegans Muscle function [137] cells antioxidant ↑ Nrf2 signaling, mitophagy Aging C. elegans ↑ Muscle function [137] antioxidant Nutrients 2021, 13, x FOR PEER REVIEW 26 of 41

Table 8. Alkaloids in the prevention of the muscle atrophy in vitro/vivo.

Alkaloids Structure Example Source Inducer Model Effect Mechanism Ref ↑ Muscle fiber size, muscle Cachexia Mice ↓ MuRF1, MAFbx [131] mass Matrine Sophora flavescens ↑ Akt/mTOR/p-FoxO3a Dexamethasone C2C12 cells ↓ Apoptosis [131] ↓ MuRF1, MAFbx

Isoquinoline alkaloids / Coptis japonica / C2C12 cells ↑ Myoblast differentiation ↑ p38/MAPK, Akt [132] ↑ p38/MAPK, Akt CT26 colon carcinoma C2C12 cells ↑ Myoblast differentiation [132,133] ↓ MuRF1, MAFbx

Magnoflorine Coptis japonica Streptozotocin Wistar rats ↑ Muscle mass ↓ MAFbx, MuRF-1 [133]

↑ p38/MAPK, Akt signaling Canadine Corydalis turtschaninovii CT26 colon carcinoma C2C12 cells ↑ Myoblast Differentiation [134] ↓ MAFbx, MuRF1 Nutrients 2021, 13, 1914 22 of 36

Tetrahydropalmatine Corydalis turtschaninovii / Table 8. Cont.C2C12 cells ↑ Myoblast Differentiation ↑ p38/MAPK, Akt signaling [135]

Alkaloids Structure Example Source Inducer Model Effect Mechanism Ref AgingAging C57BL/6 C57BL/6 mice mice ↑ Muscle↑ Muscle mass mass ↑↑ mTORmTOR signaling [[136]136] HumanHuman skeletal skeletal / myotubes, C2C12 ↑ Myotube↑ size ↑↑ mTOR signaling [136] TomatidineTomatidine TomatoesTomatoes / myotubes, C2C12 Myotube size mTOR signaling [136] Nutrients 2021, 13, x FOR PEER REVIEW cells cells 27 of 41 Nutrients Nutrients 2021 2021, ,13 13, ,x x FOR FOR PEER PEER REVIEW REVIEW 27 27 ofof 4141 ↑ Nrf2 signaling, mitophagy ↑ ↑ Nrf2 signaling, AgingAging C. elegansC. elegans Muscle↑ Muscle function function [[137]137] mitophagyantioxidant antioxidant

↑ Myoblast ConessineConessine / /HH2O2 2O2 C2C12C2C12 cells cells↑ Myoblast Differentiation ↓↓ MuRF1,MuRF1, MAFbx MAFbx [[138]138] 2 2 ↑ Differentiation ↓ ConessineConessine // HH2OO2 C2C12C2C12 cellscells ↑ MyoblastMyoblast DifferentiationDifferentiation ↓ MuRF1,MuRF1, MAFbxMAFbx [138] [138]

↑ Histone deacetylase 2 ↓ ↑ Cigarette smoke Kunming mice Inflammation↓ Inﬂammation ↑↑ HistoneHistone deacetylasedeacetylase 22 [139] CigaretteCigaretteCigarette smokesmoke smoke KunmingKunming Kunming micemice mice ↓↓ InflammationInflammation ↓ IL-8, TNF-α, NF-κB [139][[139]139] ↓↓↓ IL-8,IL-8,IL-8, TNF-TNF- TNF-αα,, NF-NF- κκBB TheophyllineTheophylline GreenGreen tea tea TheophyllineTheophylline GreenGreen teatea Cigarette smoke ↑ Histone deacetylase 2 CigaretteCigarette smokesmoke C2C12 cells ↓ Inflammation ↑↑ HistoneHistone deacetylasedeacetylase 22 [139] Cigaretteextract smoke C2C12C2C12 cellscells ↓↓ InflammationInflammation ↓↑ Histone IL-8, TNF- deacetylaseα, NF-κB 2 [139][139] extract C2C12 cells ↓ Inﬂammation ↓↓ IL-8, TNF-α, NF-κB [139] extractextract ↓ IL-8,IL-8, TNF- TNF-α, NF- κB

Picrorhiza kurroa Royle ex Picrorhiza kurroa Royle ↑ ↓ Apocynin PicrorhizaPicrorhiza kurroakurroa RoyleRoyle exex TGF-β1 C2C12 cells Myotubes↑ differentiationMyotubes TGF-β1, ROS [140] ApocyninApocyninApocynin Benth (Scrophulariaceaeex Benth ) TGF-TGF-TGF-ββ11 β1C2C12C2C12 C2C12 cellscells cells↑↑ MyotubesMyotubes differentiationdifferentiation ↓↓↓ TGF-TGF-ββ1,1,1, ROSROS [140] [[140]140] BenthBenth ((ScrophulariaceaeScrophulariaceae)) differentiation (Scrophulariaceae)

Abbreviation: Akt, protein kinase B; IL-8, Interleukin-8; MAFbx, Muscle atrophy F-box; MAPK, Mitogen-activated protein kinase; mTOR, Mammalian target of rapamycin; MuRF1, Abbreviation: Akt, protein kinase B; IL-8, Interleukin-8; MAFbx, Muscle atrophy F-box; MAPK, Mitogen-activated protein kinase; mTOR, Mammalian target of rapamycin; MuRF1, MuscleAbbreviation:Abbreviation: RING-finger Akt, Akt, protein protein protein-1; kinase kinase B; NF- IL-8, B;κ B, Interleukin-8;IL-8, Nuclear Interleukin-8; factor MAFbx, kappa-B; MuscleMAFbx, atrophyNrf2, Muscle Nuclear F-box; atrophy MAPK, factor F-box; Mitogen-activated erythroi MAPK,d-2 Mitogen-activatedrelated protein factor; kinase; ROS, mTOR, protein Reactive Mammalian kinase; oxygen targetmTOR, species; of rapamycin; Mammalian TGF-β MuRF1,, Transforming target Muscle of rapamycin; RING-ﬁnger growth factor-MuRF1, protein-1;β; Muscleκ RING-finger protein-1; NF-κB, Nuclear factor kappa-B; Nrf2, Nuclear factor erythroid-2 related factor; ROS, Reactive oxygen species; TGF-β, Transforming↑ growth factor-β; ↓ TNF-MuscleNF- αB,, Tumor NuclearRING-finger necrosis factor kappa-B;protein-1; factor- Nrf2,α ;NF- ↑, NuclearIncreaseκB, Nuclear factor or promote; erythroid-2factor kappa-B; ↓, relatedDecrease Nrf2, factor; or inhibit.Nuclear ROS, Reactive factor oxygen erythroi species;d-2 related TGF-β, Transformingfactor; ROS, growthReactive factor- oxygenβ; TNF- species;α, Tumor TGF- necrosisβ, Transforming factor-α; , Increase growth or promote;factor-β; , TNF-TNF-Decreaseαα,, TumorTumor or inhibit. necrosisnecrosis factor-factor-αα;; ↑↑,, IncreaseIncrease oror promote;promote; ↓↓,, DecreaseDecrease oror inhibit.inhibit. Nutrients 2021, 13, 1914 23 of 36

Alkaloids play an important role in the prevention of muscular atrophy by promoting myoblast differentiation. For example, isoquinoline alkaloids from Coptis japonica stimulate myoblast differentiation by promoting MyoD transcriptional activity. Magnoflorine increases expression of MyoD and MHC and subsequently stimulates myoblast differentiation via the activation of p38 MAPK and Akt signaling in C2C12 myotubes [132]. It also significantly decreases the expression of MuRF1 and MAFbx via activating the Akt/mTOR/FoxO signaling pathway in skeletal muscle of diabetic Wistar rats [133]. Cana- dine, an important alkaloid of Corydalis turtschaninovii, stimulates myoblast differentiation through the activation of p38 MAPK and Akt signaling and protects against C2C12 myotube atrophy induced by conditioned media from CT26 colon carcinoma culture by downregulating the muscle specific-E3 ligases, MAFbx and MuRF1 [134]. Tetrahydropal- matine, another compound isolated from Corydalis turtschaninovii, enhances myoblast differentiation through the activation of p38MAPK and MyoD and has the potential as a therapeutic candidate to prevent fibrosis and improve muscle regeneration and repair in C2C12 myotubes [135]. Matrine is an alkaloid isolated from the Sophora flavescens Ait.s with various pharmacological activities [141]. Matrine improves skeletal muscle atrophy by inhibiting the expression of MuRF1 and MAFbx, which is related to the activation of Akt/mTOR/FoxO3a signaling pathway in dexamethasone-treated C2C12 myotubes and cachexia mice [131]. Tomatidine, a natural small molecule alkaloid abundant in unripe tomatoes, inhibits age-related skeletal muscle atrophy via activating skeletal muscle mTORC1 signaling in C57BL/6 mice. Tomatidine also stimulates mTORC1 signaling resulting in the accumulation of protein and mitochondria, and ultimately, cell growth in C2C12 myoblasts and human skeletal myotubes. Moreover, tomatidine stimulates skeletal muscle hypertrophy and increases strength and exercise capacity [136]. Besides, it improves muscle function during aging in C. elegans by activating the Nrf2/Protein skinhead-1 pathway and upregulating mitophagy and antioxidant cellular defenses [137]. Conessine, a steroidal alkaloid, reduces dexamethasone-induced muscle atrophy by downregulating the expression of MuRF1 and MAFbx in C2C12 myotubes [138]. Theo- phylline reverses the muscle atrophy induced by 28 weeks of cigarette smoke exposure via suppressing the inflammatory effect, upregulating histone deacetylase 2 expression, and inhibiting the activation of NF-κB and p65 in Kunming mice model [139,142]. TGF-β, a classical modulator of skeletal muscle, regulates several processes in skeletal muscle disease including inhibition of myogenesis, diminution of regeneration, and induction of muscle atrophy. Apocynin, isolated and purified from Picrorhiza kurroa Royle ex Benth, prevents TGF-β-induced muscle atrophy in C2C12 myotubes through inhibiting TGF-β/Smad signaling [140]. Tinospora cordifolia extract rich in alkaloids compounds supplementation improves muscle atrophy induced by sciatic denervation of Swiss albino mice and increases myogenic differentiation of C2C12 myoblasts by alleviating oxidative stress and inflammation [143].

4.5. Triterpenoids Triterpenoids, an enormous range of bioactive compounds derived from methylpen- tanedioxylic acid with isoprene unit as the basic structural unit, have diverse physiological activity and significant pharmaceutical and industrial applications [144]. This class of natural products includes triterpenes, steroids, limonoids, quassinoids, and triterpenoidal and steroidal saponins (Table9). Ursolic acid, a pentacyclic triterpenoid abundant in apples, reduces fasting- and denervation-induced muscle atrophy by inhibiting the mRNA expression of MAFbx and MuRF1 and induces skeletal muscle hypertrophy in SD rats [145]. Meanwhile, ursolic acid and low-intensity treadmill exercise significantly improves mass of tibialis anterior and gastrocnemius muscles and decreases atrophy-related gene expression of MuRF1 and MAFbx in SD rats induced by hind limb immobilization [146]. Apple pomace extract is rich in ursolic acid and also plays an important role in the inhibition of muscle atrophy. Dietary supplement with apple pomace extracts significantly increases Nutrients 2021, 13, 1914 24 of 36

skeletal muscle strength and weight, which is related to the upregulation the expression of IGF-1 genes and downregulation of the expression of MAFbx and MuRF1 in hindlimb skeletal muscle of C57BL/6N mice. Similarly, it increases the expression of IGF-1, Akt, mTOR, and S6K1 and reduces the expression of MAFbx and MuRF1 in C2C12 myotubes [147]. Ginseng contains a variety of saponins which have beneﬁcial effects on the prevention and treatment of muscle atrophy. For example, ginsenoside Rg1, a primary active ingredient in Panax ginseng, increases the viability of mouse C2C12 myoblast cells and inhibits the expression of MAFbx and MuRF1 in the starvation-induced muscle atrophy model. Akt/mTOR/FoxO signaling pathway was involved in this process, suggesting that ginsenoside Rg1 may protect against muscle atrophy by balancing the protein degradation [148]. Like ginsenoside Rg1, ginsenoside Rg3 enhances myotube growth and suppresses the expression of MuRF1, MAFbx in TNF-α-induced muscle atrophy of C2C12 myotubes via the activation of Akt/mTOR signaling pathway. Furthermore, ginsenoside Rg3 enhances mitochondrial functions and upregulates the expression of PGC1α, Nrf1, and Tfam, and thereby protects TNF-α-induced myotube atrophy in C2C12 cells [149]. Additionally, ginsenoside Rb1 and Rb2 increase myotube growth and myogenic differentiation via activating Akt/mTOR signaling pathway [150]. Mountain ginseng, mainly including ginsenoside Rb1 followed by ginsenoside Rb2, attenuates the expression of MuRF1, MAFbx, and FoxO3a and promotes differentiation of myoblasts in dexamethasone-induced L6 cells. In SD rats exposed with dexamethasone, mountain ginseng treatment attenuates skeletal muscle atrophy and inhibits the expression of MuRF1 and MAFbx [151]. Besides, Jiang et al. found that Panax ginseng total protein suppresses the dexamethasone-induced muscle atrophy via the AMPK and PI3K/Akt signaling pathways in C2C12 myotubes [152]. Camphene, a cyclic monoterpene found in conifers, reduces starvation-induced oxidative stress and atrophy by regulating ROS generation and lipid metabolism in L6 skeletal muscle cells and SD rats [153]. Nutrients 2021, 13, 1914 25 of 36 Nutrients 2021, 13, x FOR PEER REVIEW 30 of 41

Nutrients 2021, 13, x FOR PEER REVIEW 30 of 41 Table 9. Triterpenoids in the prevention of the muscle atrophy in vitro/vivo. Nutrients 2021, 13, x FOR PEER REVIEW 30 of 41 Table 9. Triterpenoids in the prevention of the muscle atrophy in vitro/vivo. Triterpenoids Structure Example Source Inducer Model Effect Mechanism Ref Triterpenoids Structure Example Source Inducer Model Effect Mechanism Ref Table 9. Triterpenoids in theHind prevention limb of the muscle atrophy in vitro/vivo. Hind limb SD rats ↑ Muscle mass ↓ MuRF1, MAFbx [146] Table 9. Triterpenoids inimmobilization the prevention of theSD muscle rats atrophy in vitro/vivo.↑ Muscle mass ↓ MuRF1, MAFbx [146] Triterpenoids Structure Example Source immobilizationInducer Model Effect Mechanism Ref Triterpenoids Structure Example Source HindInducer limb Model ↑ MuscleEffect mass,↑ Muscle muscle mass, ↑ Muscle↑ MuscleMechanism hypertrophy hypertrophy Ref DenervationDenervation C57BL/6SD rats C57BL/6 mice mice ↑ Muscle mass ↓ MuRF1, MAFbx [146][145][145 ] immobilizationHind limb hypertrophymuscle hypertrophy ↓ MuRF1,↓ MuRF1, MAFbx MAFbx Ursolic acid acid ApplesApples SD rats ↑ Muscle mass ↓ MuRF1, MAFbx [146] immobilization ↑↑ Muscle Muscle weight, mass, muscle muscle ↑ Muscle↑ IGF-1hypertrophy Denervation/ C57BL/6NC57BL/6 mice mice ↑ Muscle weight, [145][147] strength,↑ Musclehypertrophy exerci mass,se musclecapacity ↑ Muscle↓↓ MuRF1,MuRF1, hypertrophy↑ MAFbxMAFbxIGF-1 Ursolic acid Apples Denervation/ C57BL/6 C57BL/6N mice mice muscle strength, [145][147 ] ↑ Musclehypertrophy weight, muscle ↑ IGF-1,↓ MuRF1,↓ Akt,MuRF1,↑ IGF-1 mTOR, MAFbx MAFbx S6K1 Ursolic acid Apples // C57BL/6NC2C12 cells mice ↑ Myotubesexercise differentiation capacity [147][147] strength,↑ Muscle exerci weight,se capacity muscle ↓↓ MuRF1,MuRF1,↑ IGF-1 MAFbxMAFbx / C57BL/6N mice ↑ Myotubes ↑ IGF-1,↑ IGF-1, Akt, Akt, mTOR, mTOR, S6K1 S6K1 [147] / /C2C12 cells C2C12 cells↑strength, Myotubes exerci differentiationse capacity ↓ MuRF1, MAFbx [147][147 ] ↓ ↓ differentiation ↑ IGF-1, MuRF1, Akt,MuRF1, mTOR, MAFbx MAFbx S6K1 / C2C12 cells ↑ Myotubes differentiation [147] ↓ MuRF1, MAFbx Ginsenoside Rg1 Panax ginseng Starvation C2C12 cells ↑ Myotubes differentiation ↑ Akt/mTOR/FoxO signaling [148] ↑ Myotubes ↑ Akt/mTOR/FoxO Ginsenoside Rg1 Rg1 PanaxPanax ginseng ginseng StarvationStarvation C2C12 cells C2C12 cells↑ Myotubes differentiation ↑ Akt/mTOR/FoxO signaling [148][148 ] differentiation signaling Ginsenoside Rg1 Panax ginseng Starvation C2C12 cells ↑ Myotubes differentiation ↑ Akt/mTOR/FoxO signaling [148] Panax ginseng total protein / Panax ginseng Dexamethasone C2C12 cells ↑ Glucose consumption ↑ AMPK and PI3K/Akt signaling [152]

PanaxPanax ginseng ginseng total protein total / Panax ginseng Dexamethasone C2C12 cells ↑ Glucose consumption↑ Glucose ↑ AMPK↑ andAMPK PI3K/Akt and PI3K/Akt signaling [152] / Panax ginseng Dexamethasone C2C12 cells [152] ↑ ↑ ↑ Akt/mTOR signaling PanaxGinsenoside ginsengprotein total Rg3 protein / Panax ginseng DexamethasoneTNF-α C2C12 cells ↑ Myotubes Glucose consumptiondifferentiationconsumption AMPK and PI3K/Aktsignaling signaling [152][149] ↑ PGC1α, NRF1, Tfam ↑ Akt/mTOR signaling Ginsenoside Rg3 Panax ginseng TNF-α C2C12 cells ↑ Myotubes differentiation [149] ↑ Myotubes ↑ PGC1Akt/mTOR↑ Akt/mTORα, NRF1, signaling Tfam signaling Ginsenoside Rg3 Rg3 PanaxPanax ginseng ginseng TNF-αTNF- α C2C12 cellsC2C12 cells ↑ Myotubes differentiation [149][149 ] differentiation ↑ PGC1↑ PGC1α, NRF1,α, NRF1, Tfam Tfam

Ginsenoside Rb1

Ginsenoside Rb1 Panax ginseng / C2C12 cells ↑ Myotubes differentiation ↑ Akt/mTOR signaling [150] Ginsenoside Rb1

Panax ginseng / C2C12 cells ↑ Myotubes differentiation ↑ Akt/mTOR signaling [150]

Ginsenoside Rb2 Panax ginseng / C2C12 cells ↑ Myotubes differentiation ↑ Akt/mTOR signaling [150]

Ginsenoside Rb2 Ginsenoside Rb2 Abbreviation: Akt, protein kinase B; FoxO, Forkhead box O; IGF-1, Insulin-like growth factor 1; PI3K, Phosphoinositide 3-kinase; MAFbx, Muscle atrophy F-box; mTOR, Mammalian target of rapamycin; MuRF1, Muscle RING-finger protein-1; NRF1, Nuclear respiratory factor 1; PGC1α, Peroxisome proliferator-activated receptor γ coactiva-tor-1α; S6K1, Ribosomal

Abbreviation:protein S6 kinase; Akt, SD, protein Sprague kinase Dawley; B; FoxO, ↑, Increase Forkhead or boxpromote; O; IGF- ↓, 1,Decrease Insulin-like or inhibit. growth factor 1; PI3K, Phosphoinositide 3-kinase; MAFbx, Muscle atrophy F-box; mTOR, Mammalian targetAbbreviation: of rapamycin; Akt, protein MuRF1, kinase Muscle B; RING-fingerFoxO, Forkhead protein-1; box O; NRF1, IGF-1, Nuclear Insulin-like respiratory growth factorfactor 1;1; PGC1PI3K,α Phosphoinositide, Peroxisome proliferator-activated 3-kinase; MAFbx, receptorMuscle atrophyγ coactiva-tor-1 F-box; mTOR,α; S6K1, Mammalian Ribosomal proteintarget of S6 rapamycin; kinase; SD, MuRF1, Sprague Muscle Dawley; RING-finger ↑, Increase protein-1;or promote; NRF1, ↓, Decrease Nuclear or respiratory inhibit. factor 1; PGC1α, Peroxisome proliferator-activated receptor γ coactiva-tor-1α; S6K1, Ribosomal protein S6 kinase; SD, Sprague Dawley; ↑, Increase or promote; ↓, Decrease or inhibit. Nutrients 2021, 13, x FOR PEER REVIEW 30 of 41

Table 9. Triterpenoids in the prevention of the muscle atrophy in vitro/vivo.

Triterpenoids Structure Example Source Inducer Model Effect Mechanism Ref Hind limb SD rats ↑ Muscle mass ↓ MuRF1, MAFbx [146] immobilization ↑ Muscle mass, muscle ↑ Muscle hypertrophy Denervation C57BL/6 mice [145] hypertrophy ↓ MuRF1, MAFbx Ursolic acid Apples ↑ Muscle weight, muscle ↑ IGF-1 / C57BL/6N mice [147] strength, exercise capacity ↓ MuRF1, MAFbx ↑ IGF-1, Akt, mTOR, S6K1 / C2C12 cells ↑ Myotubes differentiation [147] ↓ MuRF1, MAFbx

Ginsenoside Rg1 Panax ginseng Starvation C2C12 cells ↑ Myotubes differentiation ↑ Akt/mTOR/FoxO signaling [148]

PanaxNutrients ginseng2021 total, 13, 1914protein / Panax ginseng Dexamethasone C2C12 cells ↑ Glucose consumption ↑ AMPK and PI3K/Akt signaling [152] 26 of 36

↑ Akt/mTOR signaling Ginsenoside Rg3 Panax ginseng TNF-α C2C12 cells ↑ Myotubes differentiation [149] Table 9. Cont. ↑ PGC1α, NRF1, Tfam

Triterpenoids Structure Example Source Inducer Model Effect Mechanism Ref

Ginsenoside Rb1 Rb1

Panax ginseng / C2C12 cells ↑ Myotubes differentiation↑ Myotubes ↑ Akt/mTOR signaling [150] Panax ginseng / C2C12 cells ↑ Akt/mTOR signaling [150] differentiation

Ginsenoside Rb2 Rb2

Abbreviation:Abbreviation: Akt, Akt, protein kinase kinase B; B; FoxO, FoxO, Forkhead Forkhead box O; box IGF-1, O; IGF- Insulin-like1, Insulin-like growth factor growth 1; PI3K, factor Phosphoinositide 1; PI3K, Phosphoinositide 3-kinase; MAFbx, 3-kinase Muscle; atrophy MAFbx, F-box; Muscle mTOR, atrophy Mammalian F-box; target mTOR, of rapamycin; Mammalian MuRF1, targetMuscle of rapamycin; RING-ﬁnger MuRF1, protein-1; Muscle NRF1,Nuclear RING-finger respiratory protein-1; factor1; NRF1, PGC1 αNuclear, Peroxisome respiratory proliferator-activated factor 1; PGC1 receptorα, Peroxisomeγ coactiva-tor-1 proliferator-activatedα; S6K1, Ribosomal proteinreceptor S6 γ kinase; coactiva-tor-1 SD, Spragueα; S6K1, Dawley; Ribosomal↑, Increase or ↓ proteinpromote; S6 kinase;, Decrease SD, orSprague inhibit. Dawley; ↑, Increase or promote; ↓, Decrease or inhibit. Nutrients 2021, 13, 1914 27 of 36

4.6. Others α-Ketoglutarate rescues corticosterone-induced skeletal muscle atrophy in vitro (C2C12 myotubes) and in vivo (C57BL/6J mice) through inhibiting the expression of MuRF1 and MAFbx [154] (Table 10). Cinnamaldehyde protects H2O2-induced C2C12 myotubes atrophy by inhibiting the expression of MuRF1 and MAFbx and maintaining the balance of cellular redox [155]. Fucoxanthin, a carotenoid produced by Undaria pinnatiﬁda and Phaeodactylum tricornutum, increases tibialis anterior muscle and gastrocnemius muscle weight and protects against dexamethasone-induced muscle atrophy through reducing oxidative stress in tibialis anterior muscle in ICR mice [156]. The Arctium lappa L. fruit extract rich in arctiin and arctigenin improves cancer-induced muscle atrophy by inhibiting NutrientsNutrients 2021 2021, ,13 13, ,x x FOR FOR PEER PEER REVIEW REVIEW skeletal muscle loss in BALB/c mice. In C2C12 myoblasts and 3T3-L1 cells, it decreases the 32 32 ofof 4141

expression of muscle degradation factors (MAFbx and MuRF1) and increases adipocytes differentiation factors, respectively [157].

Table 10. Other phytochemicals in the prevention of the muscle atrophy in vitro/vivo. TableTable 10. 10. Other Other phytochemicals phytochemicals in in the the prevention prevention of of the the muscle muscle atrophy atrophy in in vitro/vivo. vitro/vivo. Others Structure Example Source Inducer Model Effect Mechanism Ref OthersOthers StructureStructure ExampleExample Source Source InduceInducerr ModelModel EffectEffect MechanismMechanism RefRef C57BL/6J C57BL/6J↑C57BL/6JMuscle mass mice mice ↓ MuRF1,↑ MAFbx↑ Muscle Muscle mass mass [154 ] ↓↓ MuRF1, MuRF1, MAFbx MAFbx [154] [154] mice αα-Ketoglutarate-Ketoglutarateα-Ketoglutarate / // CorticosteroneCorticosteroneCorticosterone C2C12↑C2C12Myotube cells cells ↑↑ Myotube Myotube size size ↓↓ MuRF1, MuRF1, MAFbx MAFbx [154] [154] C2C12 cells ↓ MuRF1, MAFbx [154] size

↓↓ MuRF1, MuRF1, MAFbx MAFbx 2 2 ↑ Myotube ↓ MuRF1,↑ MAFbx CinnamaldehydeCinnamaldehydeCinnamaldehyde CinnamonCinnamonCinnamon H2O2 HH2OO2C2C12 cells C2C12C2C12 cells cells ↑ Myotube Myotube diameter diameter[155] [155][155] diameter ↓ Oxidative stress ↓↓ Oxidative Oxidative stress stress

Undaria Fucoxanthin Dexamethasone ICR mice ↑ Muscle mass ↓ Oxidative stress [156] FucoxanthinFucoxanthin UndariaUndariapinnatiﬁda pinnatifida pinnatifida Dexamethasone Dexamethasone ICRICR mice mice ↑↑ Muscle Muscle mass mass ↓↓ Oxidative Oxidative stress stress [156] [156]

↑ ↓ Abbreviation:Abbreviation:Abbreviation: H2 H OH22O,O Hydrogen22, ,Hydrogen Hydrogen peroxide; peroxide; peroxide; MAFbx, MAFbx, MAFbx, Muscle Muscle atrophyMuscle atrophy F-box;atrophy MuRF1, F- F-box;box; Muscle MuRF1, MuRF1, RING-ﬁnger Muscle Muscle RI protein-1;RING-fingerNG-finger, Increase protein-1; protein-1; or promote; ↑ ↑, ,Increase Increase, or or promote; promote; ↓ ↓, ,Decrease Decrease or or inhibit. inhibit. Decrease or inhibit.

Collectively, phytochemicals play an essential role in the prevention and treatment of muscle atrophy, especially in reducing muscle protein degradation and promoting muscle protein synthesis [17,18]. Their primary mechanism includes the enhancement of myoblast differentiation, prevention of muscle protein degradation, the promotion of protein synthesis and myogenesis, anti-inflammation, anti-oxidation, and the downregulation of atrophy-related gene expression. Nevertheless, because the efficacy and molecular mechanisms of most phytochemicals have been examined only in preclinical trials, either in vitro or in vivo, the clinical evidence is not sufficient and is therefore urgently needed. In addition, there is little evidence supporting the structure-function relationship of phytochemicals in skeletal muscle atrophy. The exact relationship between the structure of phytochemicals and their anti-atrophy effect needs to be further investigated.

5. Probiotics Leukemia BALB/c mice, characterized by a loss of fat mass, muscle atrophy, anorexia, and inflammation, has severe dysbiosis of Lactobacillus. Whereafter, oral supplementation of Lactobacillus (L. reuteri 100-23 and L. gasseri 311476) significantly reduced the expression of atrophy markers (MAFbx and MuRF1) and inflammatory cytokines (IL-6, monocyte chemoattractant protein-1, Interleukin-4, and granulocyte colony-stimulating factor) [158]. In ICR mice, oral administration of Lactobacillus plantarum TWK10 for six weeks increases muscle mass and improves exercise performance [159]. Those results suggest that Lacto- bacillus could protect muscle against atrophy and its mechanism is related to decreased systemic inflammation and increased muscle mass. Inflammatory bowel disease and Crohn’s disease patients suffer from intestinal injury and inflammation-induced muscle atrophy. Oral supplementation Escherichia coli significantly decreases the expression of MAFbx and MuRF1 in B. thailandensis, S. Typhimurium or Nutrients 2021, 13, 1914 28 of 36

dextran sulfate sodium-induced muscle atrophy via the activation of the IGF-1/PI3K/Akt signaling pathway in skeletal muscle tissues [160]. Oral administration of Lactobacillus casei LC122 and Bifidobacterium ongum BL986 for 12 weeks enhances muscle strength and function in C57BL/6 mice [161]. In conclusion, probiotics might potentially constitute a future therapeutic target in the modulation of muscle wasting. Compared with the above-mentioned dietary nutrients and phytochemicals including polyphenols, flavonoids, polysaccharides, alkaloids, and triterpenoids, knowledge regard- ing the mechanisms of probiotics is unclear and lacking, while probiotics exert beneficial effect on skeletal muscle atrophy. In this regard, it will be of great interest to delineate the underlying anti-atrophy mechanisms of probiotics in future studies. Fermented foods, particularly dairy foods, are commonly used as probiotic carriers. For example, the yogurt or fermented milk contains different combinations of probiotics including Lactobacillus bulgaricus, Lactobacillus delbrueckii, and Bifidobacterium bifidum [162]. Iwasa et al. reported that Lactobacillus helveticus–fermented milk prevents acute exercise- induced muscle damage [163]. Dietary intake of probiotic kimchi, a representative fermented product containing beneficial bacteria, such as Leuconostoc mesenteroides CJ LM119 and Lactobacillus plantarum CJ LP133, promotes the amelioration of cachexia-induced muscle atrophy [164]. In addition, prebiotics is known to alter the composition and/or activity of the intestinal microbiota and bring possible benefits to the individual’s muscle health. For example, a randomized controlled double-blind study demonstrated that 13 weeks intake of inulin and fructooligosaccharides complex increases the grip strength in elderly people over 65 years old [165]. Besides, the gut microbiota plays an important role in maintaining host physiology homeostasis by regulating multiple processes, including nutrient absorption, inflammation, oxidative stress, immune function, and anabolic balance. Lahiri et al. found that the expression of MAFbx and MuRF-1 is upregulating in germ-free mice compared to pathogen-free mice. However, when transplanting the gut microbiota from pathogen-free mice into germ-free mice, the skeletal muscle atrophy markers are significantly reduced, and the skeletal muscle mass and oxidative metabolic capacity are improved in C57BL/6J male mice [166], suggesting that gut microbiota may serve an essential role in preventing muscle atrophy. Gut microbiota and their metabolites (e.g., short-chain fatty acids) are likely to engage multiple converging pathways to regulate host muscle growth and function [166]. Considering the reported anti-muscle atrophy effect of some nutraceuticals, such as resveratrol and epicatechin, and the fact that they could modulate the gut microbiome composition and increase circulating levels of short-chain fatty acids [167,168], it is likely that they may improve muscle atrophy by regulating the gut microbiota and their metabolites; nevertheless, future confirmatory studies are needed.

6. Conclusions and Perspective The nutraceuticals reported in this review have been shown to have predominantly preventive effects on muscle atrophy via the attenuation of muscle protein degradation and the promotion of protein synthesis and myogenesis. The mechanisms are associated with the inhibition of inﬂammation, oxidative stress, glucocorticoid, myostatin, and muscle atrophy-related genes and the activation of IGF-1 signaling pathway. Nutraceuticals with a relevant role in the prevention of muscle protein loss and maintenance of skeletal muscle mass open an important implication in designing appropriate nutritional therapeutic approaches for skeletal muscle atrophy and other muscle health problem. Although, over the past few decades, the cellular and molecular mechanisms of muscle atrophy have been studied extensively and the beneﬁcial effects of certain nutraceuticals on muscle atrophy in vitro or in vivo have been demonstrated unequivocally, we remain far from having a marketed nutraceutical compounds for muscle atrophy treatment. Future research can focus on the following points: (a) To examine anti-muscle atrophy action and dose of these dietary components in clinical trials as the potentiality of most nutraceu- Nutrients 2021, 13, 1914 29 of 36

ticals has been investigated only in preclinical trials and clinical trials are lacking, and screen the most promising functional ingredient candidates for humans. (b) To study the bioavailability of functional ingredients and their effects on whole body metabolism. (c) To explore more active ingredients with protective ability to muscle atrophy through different experimental methods including 3D cell models, organoid models, and in silico high-throughput screening. (d) To open new frontiers in counteracting imbalances in muscle protein homeostasis by applying new omics science, such as nutrigenomics, which describes the epigenetic mechanisms of action of those nutraceuticals. These will contribute to a more detailed comprehension of muscle atrophy-preventive effects of dietary components, boosting the development of functional ingredients as a tool to counteract muscle atrophy.

Author Contributions: Y.W., K.H., and T.T. wrote the manuscript; Y.W., Q.L., H.Q., S.-G.K., K.H., and T.T. reviewed the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the National Key R&D Program of China (grant number: 2017YFC1600901) and was supported by the 2115 Talent Development Program of China Agricul- tural University. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conﬂicts of Interest: The authors have no conﬂict of interest to declare.

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