stilbenes and Muscular-Atrophy

Skeletal muscle atrophy is the consequence of various conditions, such as disuse, denervation, fasting, aging, and disease. Even if the underlying molecular mechanisms are still not fully understood, an elevated oxidative stress related to mitochondrial dysfunction has been proposed as one of the major contributors to skeletal muscle atrophy. Researchers have described various forms of nutritional supplementation to prevent oxidative stress-induced muscle wasting. Among a variety of nutrients, attention has also focused on polyphenols, a wide range of plant-based compounds with antioxidant and inflammatory properties, many of which have beneficial effects on human health and might retard skeletal muscle loss and function impairment. The purpose of this review is to describe polyphenol actions in skeletal muscle atrophy prevention. Published articles from the last 10 years were searched on PubMed and other databases. Polyphenols are important molecules that should be considered when discussing possible strategies against muscle atrophy. In particular, the collected studies describe, for each polyphenol subclass, the beneficial effect on muscle mass preservation in various skeletal muscle disorders. In these examples, the polyphenol compounds appear to mainly act by reversing mitochondrial dysfunction. Given that the current information on polyphenols is mostly restricted to basic studies, more comprehensive research and additional studies should be performed to clarify their mechanisms of action in improving skeletal muscle functions during atrophy.

Topics: Acids, Carbocyclic; Animals; Anti-Inflammatory Agents; Antioxidants; Diet; Dietary Supplements; Flavonoids; Fruit; Humans; Mitochondria, Muscle; Muscle, Skeletal; Muscular Atrophy; Polyphenols; Stilbenes; Vegetables

Chronic kidney disease (CKD) is often associated with muscle atrophy. However, the underlying molecular mechanisms are still not well understood. Here, we treated 5/6-nephrectomized (5/6Nx) rats with resveratrol and found that this treatment greatly improves renal function as evidenced by reduced proteinuria and cystatin C. Moreover, resveratrol ameliorates renal fibrosis by reducing transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF). Meanwhile, muscle atrophy in these 5/6Nx rats was largely attenuated by resveratrol. Immunoprecipitation revealed that SIRT1 physically interacts with FoxO1 in muscle, and this interaction was weakened in 5/6Nx rats. As a consequence, acetylated FoxO1 was increased in muscle of 5/6Nx rats. The application of resveratrol markedly reverses this trend. These data point out that SIRT1 is a key factor for linking renal disease and muscle atrophy. Indeed, both renal dysfunction and muscle atrophy were further aggravated by 5/6Nx in Sirt1

Topics: Animals; Forkhead Box Protein O1; Mice; Muscular Atrophy; Nerve Tissue Proteins; Rats; Renal Insufficiency, Chronic; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes

Decrease in activity stress induces skeletal muscle atrophy. A previous study showed that treatment with resveratrol inhibits muscular atrophy in mdx mice, a model of DMD. However, almost all studies using resveratrol supplementation have only looked at adaptive changes in the muscle weight. The present study was designed to elucidate whether the resveratrol-inducing attenuation of skeletal muscle actually reflects the adaptation of muscle fibers themselves, based on the modulation of atrogin-1- or p62-dependent signaling. Mice were fed either a normal diet or 0.5% resveratrol diet. One week later, the right sciatic nerve was cut. The wet weight, mean fiber area, and amount of atrogin-1 and p62 proteins were examined in the gastrocnemius muscle at 14 days after denervation. The 0.5% resveratrol diet significantly prevented denervation-induced decreases in both the muscle weight and fiber atrophy. In addition, dietary resveratrol suppressed the denervation-induced atrogin-1 and p62 immunoreactivity. In contrast, 0.5% resveratrol supplementation did not significantly modulate the total protein amount of atrogin-1 or p62 in the denervated muscle of mice. Resveratrol supplementation significantly prevents muscle atrophy after denervation in mice, possibly due to the decrease in atrogin-1 and p62-dependent signaling.

Topics: Animals; Dietary Supplements; Humans; Mice, Inbred mdx; Muscle Denervation; Muscle Fibers, Skeletal; Muscle Proteins; Muscular Atrophy; Resveratrol; Signal Transduction; SKP Cullin F-Box Protein Ligases; Stilbenes; Transcription Factor TFIIH; Transcription Factors

Skeletal muscle atrophy is an important clinical characteristic of chronic kidney disease (CKD); however, at present, the therapeutic approaches to muscle atrophy induced by CKD are still at an early stage of development. Resveratrol is used to attenuate muscle atrophy in other experimental models, but the effects on a CKD model are largely unknown. Here, we showed that resveratrol prevented an increase in MuRF1 expression and attenuated muscle atrophy in vivo model of CKD. We also found that phosphorylation of NF-κB was inhibited at the same time. Dexamethasone-induced MuRF1 upregulation was significantly attenuated in C2C12 myotubes by resveratrol in vitro, but this effect on C2C12 myotubes was abrogated by a knockdown of NF-κB, suggesting that the beneficial effect of resveratrol was NF-κB dependent. Our findings provide novel information about the ability of resveratrol to prevent or treat muscle atrophy induced by CKD.

Topics: Animals; Dose-Response Relationship, Drug; Mice; Mice, Inbred C57BL; Muscle Proteins; Muscular Atrophy; NF-kappa B; Renal Insufficiency, Chronic; Resveratrol; Signal Transduction; Stilbenes; Tripartite Motif Proteins; Ubiquitin-Protein Ligases

Muscle atrophy occurs in several pathologic conditions such as diabetes and chronic obstructive pulmonary disease (COPD), as well as after long-term clinical administration of synthesized glucocorticoid, where increased circulating glucocorticoid accounts for the pathogenesis of muscle atrophy. Others and we previously reported mitochondrial dysfunction in muscle atrophy-related conditions and that mitochondria-targeting nutrients efficiently prevent kinds of muscle atrophy. However, whether and how mitochondrial dysfunction involves glucocorticoid-induced muscle atrophy remains unclear. Therefore, in the present study, we measured mitochondrial function in dexamethasone-induced muscle atrophy in vivo and in vitro, and we found that mitochondrial respiration was compromised on the 3rd day following after dexamethasone administration, earlier than the increases of MuRF1 and Fbx32, and dexamethasone-induced loss of mitochondrial components and key mitochondrial dynamics proteins. Furthermore, dexamethasone treatment caused intracellular ATP deprivation and robust AMPK activation, which further activated the FOXO3/Atrogenes pathway. By directly impairing mitochondrial respiration, FCCP leads to similar readouts in C2C12 myotubes as dexamethasone does. On the contrary, resveratrol, a mitochondrial nutrient, efficiently reversed dexamethasone-induced mitochondrial dysfunction and muscle atrophy in both C2C12 myotubes and mice, by improving mitochondrial function and blocking AMPK/FOXO3 signaling. These results indicate that mitochondrial dysfunction acts as a central role in dexamethasone-induced skeletal muscle atrophy and that nutrients or drugs targeting mitochondria might be beneficial in preventing or curing muscle atrophy.

Topics: Animals; Cell Differentiation; Cell Line; Dexamethasone; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Atrophy; Resveratrol; Signal Transduction; Stilbenes

Muscle atrophy poses a serious concern to patients inflicted with inflammatory diseases. There is now increasing evidence which suggests a vital role for tumor necrosis factor alpha (TNF-α) in muscle pathology associated with impairment of differentiation and muscle wasting. Resveratrol has been an ascribed inhibitory effect on glucocorticoid-induced muscle atrophy in vitro, but the influence of resveratrol on the growth of C2C12 myotubes exposed to TNF-α remains unclear. The present study aimed to investigate the involvement of TNF-α in the regulation of skeletal muscle hypertrophy and atrophy, and the possibility to interfere with such modulations by means of resveratrol supplementation. For this purpose, C2C12 myotubes were treated with TNF-α in the presence or absence of resveratrol. Myotube treatment with TNF-α contributes to both hyperexpression of the muscle-specific ubiquitin ligase MAFbx and MuRF1, and these alterations are linked to a decrease of anabolic targets (Akt, mTOR, p70S6k and 4E-BP1) and an increase of catabolic targets (FoxO1, FoxO3a, MAFbx and MuRF1). Resveratrol supplementation effectively counteracts TNF-α induced muscle protein loss and reverses declining expression of Akt, mTOR, p70S6K, 4E-BP1and FoxO1, but exerts no influence of FoxO3a expression. Our study demonstrates that resveratrol can reverse the muscle cell atrophy caused by TNF-α through regulation of the Akt/mTOR/FoxO1 signaling pathways, followed by inhibition of the atrophy-related ubiquitin ligase. Our findings suggested that resveratrol could represent a possible strategy to improve muscle mass.

Topics: Animals; Cell Line; Forkhead Box Protein O1; Forkhead Transcription Factors; Mice; Muscle Fibers, Skeletal; Muscle Proteins; Muscular Atrophy; Proto-Oncogene Proteins c-akt; Resveratrol; RNA, Messenger; RNA, Small Interfering; Signal Transduction; SKP Cullin F-Box Protein Ligases; Stilbenes; TOR Serine-Threonine Kinases; Tripartite Motif Proteins; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases

Aging is associated with poor skeletal muscle regenerative ability following extended periods of hospitalization and other forms of muscular disuse. Resveratrol (3,5,4'-trihydroxystilbene) is a natural phytoalexin which has been shown in skeletal muscle to improve oxidative stress levels in muscles of aged rats. As muscle disuse and reloading after disuse increases oxidative stress, we hypothesized that resveratrol supplementation would improve muscle regeneration after disuse. A total of thirty-six male Fisher 344 × Brown Norway rats (32 mo.) were treated with either a water vehicle or resveratrol via oral gavage. The animals received hindlimb suspension for 14 days. Thereafter, they were either sacrificed or allowed an additional 14 day period of cage ambulation during reloading. A total of six rats from the vehicle and the resveratrol treated groups were used for the hindlimb suspension and recovery protocols. Furthermore, two groups of 6 vehicle treated animals maintained normal ambulation throughout the experiment, and were used as control animals for the hindlimb suspension and reloading groups. The data show that resveratrol supplementation was unable to attenuate the decreases in plantaris muscle wet weight during hindlimb suspension but it improved muscle mass during reloading after hindlimb suspension. Although resveratrol did not prevent fiber atrophy during the period of disuse, it increased the fiber cross sectional area of type IIA and IIB fibers in response to reloading after hindlimb suspension. There was a modest enhancement of myogenic precursor cell proliferation in resveratrol-treated muscles after reloading, but this failed to reach statistical significance. The resveratrol-associated improvement in type II fiber size and muscle mass recovery after disuse may have been due to decreases in the abundance of pro-apoptotic proteins Bax, cleaved caspase 3 and cleaved caspase 9 in reloaded muscles. Resveratrol appears to have modest therapeutic benefits for improving muscle mass after disuse in aging.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; bcl-2-Associated X Protein; Caspase 3; Male; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Organ Size; Rats; Rats, Inbred F344; Resveratrol; Stilbenes

The abnormalities associated with cancer cachexia include anorexia, weight loss, muscle loss and atrophy, anaemia and alterations in carbohydrate, lipid and protein metabolism. The aim of the present investigation was to examine the anti-wasting effects of some nutraceuticals such as genistein, resveratrol, epigallocatechin gallate and diallyl sulphide (DAS).. The in vitro effects of these nutraceuticals on proteolysis were examined in muscle cell cultures submitted to hyperthermia. The in vivo effects of DAS were also tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma).. Although all the nutraceuticals tested inhibited muscle proteolysis, the most promising effects were related with DAS. In vivo administration of DAS only leads to a small improvement in tibialis muscle and heart weights; however, administration of DAS to healthy animals increased all muscle weights, this being associated with a decreased gene expression of proteolytic systems components.. It may be suggested that DAS could be used to improve muscle mass during healthy conditions.

Topics: Allyl Compounds; Animals; Anorexia; Cachexia; Catechin; Cells, Cultured; Dietary Supplements; Genistein; Male; Muscle, Skeletal; Muscular Atrophy; Neoplasms; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sulfides; Weight Loss

Hypercatabolic syndrome is a biochemical state characterized by a imbalance between catabolism and anabolism in favor of catabolism. Diabetes is an example of hypercatabolic syndrome with presence of decreased insulin level or impaired insulin signaling besides increased inflammatory cytokines. One of the significant outcomes of this state is accelerated protein degradation and muscle wasting. Increased ubiquitin-proteasomal system activity is the major responsible for the muscle wasting. Increase in expression and activities of proteasomal proteins in diabetes had been determined. NF-κB transcription factor mediated inflammation and oxidative stress accompanies proteasomal activity increase. Oxidative stress continuously produces substrate for proteasomes by causing protein oxidation. An intervention that inhibits proteasomal activity, suppressing inflammation and oxidative stress may form a solution in order to prevent muscle wasting. Therefore, I am considering that the combined use of bortezomib, a proteasome inhibitor and an anti-inflammatory with resveratrol, an antioxidant and anti-inflammatory, could prevent diabetes induced muscle wasting. This combination may be a novel therapeutic approach for muscle wasting.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Boronic Acids; Bortezomib; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Humans; Inflammation; Models, Biological; Muscular Atrophy; Protease Inhibitors; Proteasome Endopeptidase Complex; Pyrazines; Rats; Resveratrol; Stilbenes

The mechanism by which cancer mediates muscle atrophy has been delineated in the past 3 decades and includes a prominent role of tumor-derived cytokines, such as IL-6, TNFα, and IL-1. These cytokines interact with their cognate receptors on muscle to activate the downstream transcription factor NF-κB and induce sarcomere proteolysis. Experimentally, inhibiting NF-κB signaling largely prevents cancer-induced muscle wasting, indicating its prominent role in muscle atrophy. Resveratrol, a natural phytoalexin found in the skin of grapes, has recently been shown to inhibit NF-κB in cancer cells, which led us to hypothesize that it might have a protective role in cancer cachexia. Therefore, we investigated whether daily oral resveratrol could protect against skeletal muscle loss and cardiac atrophy in an established mouse model. We demonstrate resveratrol inhibits skeletal muscle and cardiac atrophy induced by C26 adenocarcinoma tumors through its inhibition of NF-κB (p65) activity in skeletal muscle and heart. These studies demonstrate for the first time the utility of oral resveratrol therapy to provide clinical benefit in cancer-induced atrophy through the inhibition of NF-κB in muscle. These findings may have application in the treatment of diseases with parallel pathophysiologies such as muscular dystrophy and heart failure.

Topics: Adenocarcinoma; Administration, Oral; Animals; Body Composition; Cachexia; Cell Line, Tumor; Dose-Response Relationship, Drug; Echocardiography; Female; Gene Expression Regulation, Enzymologic; Heart; Mice; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Myocardium; Neoplasm Transplantation; Random Allocation; Resveratrol; RNA, Messenger; Stilbenes; Transcription Factor RelA; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Weight Loss

Long-term spaceflight induces hypokinesia and hypodynamia, which, along microgravity per se, result in a number of significant physiological alterations, such as muscle atrophy, force reduction, insulin resistance, substrate use shift from fats to carbohydrates, and bone loss. Each of these adaptations could turn to serious health deterioration during the long-term spaceflight needed for planetary exploration. We hypothesized that resveratrol (RES), a natural polyphenol, could be used as a nutritional countermeasure to prevent muscle metabolic and bone adaptations to 15 d of rat hindlimb unloading. RES treatment maintained a net protein balance, soleus muscle mass, and soleus muscle maximal force contraction. RES also fully maintained soleus mitochondrial capacity to oxidize palmitoyl-carnitine and reversed the decrease of the glutathione vs. glutathione disulfide ratio, a biomarker of oxidative stress. At the molecular level, the protein content of Sirt-1 and COXIV in soleus muscle was also preserved. RES further protected whole-body insulin sensitivity and lipid trafficking and oxidation, and this was likely associated with the maintained expression of FAT/CD36, CPT-1, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in muscle. Finally, chronic RES supplementation maintained the bone mineral density and strength of the femur. For the first time, we report a simple countermeasure that prevents the deleterious adaptations of the major physiological functions affected by mechanical unloading. RES could thus be envisaged as a nutritional countermeasure for spaceflight but remains to be tested in humans.

Topics: Adipose Tissue; Animals; Biological Availability; Biomarkers; Body Temperature Regulation; Bone Density; Enzyme Inhibitors; Glucose Tolerance Test; Hindlimb Suspension; Inflammation; Insulin Resistance; Male; Muscle, Skeletal; Muscular Atrophy; Physical Conditioning, Animal; Rats; Rats, Wistar; Resveratrol; Stilbenes

Hindlimb suspension (HLS) elicits muscle atrophy, oxidative stress, and apoptosis in skeletal muscle. Increases in oxidative stress can have detrimental effects on muscle mass and function, and it can potentially lead to myonuclear apoptosis. Resveratrol is a naturally occurring polyphenol possessing both antioxidant and antiaging properties. To analyze the capacity of resveratrol to attenuate oxidative stress, apoptosis and muscle force loss were measured following 14 days of HLS. Young (6 mo) and old (34 mo) rats were administered either 12.5 mg·kg(-1)·day(-1) of trans-resveratrol, or 0.1% carboxymethylcellulose for 21 days, including 14 days of HLS. HLS induced a significant decrease in plantarflexor isometric force, but resveratrol blunted this loss in old animals. Resveratrol increased gastrocnemius catalase activity, MnSOD activity, and MnSOD protein content following HLS. Resveratrol reduced hydrogen peroxide and lipid peroxidation levels in muscles from old animals after HLS. Caspase 9 abundance was reduced and Bcl-2 was increased, but other apoptotic markers were not affected by resveratrol in the gastrocnemius muscle after HLS. The data indicate that resveratrol has a protective effect against oxidative stress and muscle force loss in old HLS animals; however, resveratrol was unable to attenuate apoptosis following HLS. These results suggest that resveratrol has the potential to be an effective therapeutic agent to treat muscle functional decrements via improving the redox status associated with disuse.

Topics: Age Factors; Aging; Animals; Apoptosis; Catalase; Enzyme-Linked Immunosorbent Assay; Hindlimb Suspension; Hydrogen Peroxide; Lipid Peroxidation; Male; Muscle, Skeletal; Muscular Atrophy; Oxidative Stress; Rats; Resveratrol; Signal Transduction; Stilbenes; Superoxide Dismutase