Age-related Loss Of Skeletal Muscle Research Articles

The Vicious Cycle of Myostatin Signaling in Sarcopenic Obesity: Myostatin Role in Skeletal Muscle Growth, Insulin Signaling and Implications for Clinical Trials.

The age-related loss of skeletal muscle (sarcopenia) is a major health concern as it is associated with physical disability, metabolic impairments, and increased mortality. The coexistence of sarcopenia with obesity, termed 'sarcopenic obesity', contributes to skeletal muscle insulin resistance and the development of type 2 diabetes, a disease prevalent with advancing age. Despite this knowledge, the mechanisms contributing to sarcopenic obesity remain poorly understood, preventing the development of targeted therapeutics. This article will discuss the clinical and physiological consequences of sarcopenic obesity and propose myostatin as a potential candidate contributing to this condition. A special emphasis will be placed on examining the role of myostatin signaling in impairing both skeletal muscle growth and insulin signaling. In addition, the role of myostatin in regulating muscle-to fat cross talk, further exacerbating metabolic dysfunction in the elderly, will be highlighted. Lastly, we discuss how this knowledge has implications for the design of myostatin-inhibitor clinical trials.

Measurements of skeletal muscle mass and power are positively related to a Mediterranean dietary pattern in women.

SummaryThe age-related loss of skeletal muscle and function are risk factors for osteoporosis and fractures. We found that higher adherence to the Mediterranean diet score was significantly associated with greater fat-free mass and leg explosive power suggesting a role for the Mediterranean Diet in prevention of loss of muscle outcomes.IntroductionThe loss of skeletal muscle mass, strength, and function with age are contributing risk factors for the onset of sarcopenia, frailty, osteoporosis, fractures, and mortality. Nutrition may affect the progression and trajectory of these changes in skeletal muscle but the role of the micronutrient-rich Mediterranean diet (MD) has hardly been investigated in relation to these muscle outcomes.MethodsWe examined associations between the MD score (MDS) and FFM% (fat-free mass / weight × 100), FFMI (fat-free mass/height2), hand grip strength, and leg explosive power (LEP, watts/kg) in a cross-sectional study in 2570 women aged 18–79 years from the TwinsUK study. Measurements of body composition were made using dual-energy X-ray absorptiometry and dietary intake assessed by a food frequency questionnaire. FFM%, FFMI, grip strength, and LEP were compared across quartiles of the MDS after adjustment for covariates, with CRP measured in a subgroup (n = 1658).ResultsHigher adherence to the MDS was positively associated with measurements of muscle outcomes, with significant differences of 1.7 % for FFM% and 9.6 % for LEP (P trend <0.001), comparing extreme quartiles of intake, but not with grip strength or CRP concentrations.ConclusionsFor the first time in a northern European population, we have observed significant positive associations between the MDS and FFM% and LEP in healthy women that are potentially clinically relevant, independent of the factors known to influence muscle outcomes. Our findings emphasize the potential role for overall diet quality based on the MD in the prevention of age-related loss of skeletal muscle outcomes.

Treatment with rGDF11 does not improve the dystrophic muscle pathology of mdx mice.

BackgroundDuchenne muscular dystrophy (DMD) is an inherited lethal muscle wasting disease characterized by cycles of degeneration and regeneration, with no effective therapy. Growth differentiation factor 11 (GDF11), a member of the TGF-β superfamily and myostatin homologous, has been reported to have the capacity to reverse age-related skeletal muscle loss. These initial findings led us to investigate the ability of GDF11 to promote regeneration in the context of muscular dystrophy and determine whether it could be a candidate to slow down or reverse the disease progression in DMD.ResultsHere, we delivered recombinant GDF11 (rGDF11) to dystrophin-deficient mice using the intra-peritoneal route for 30 days and evaluated histology and function in both steady-state and cardiotoxin-injured muscles. Our data confirmed that treatment with rGDF11 resulted in elevated levels of this factor in the circulation. However, this had no effect on muscle contractility nor on muscle histology. Moreover, no difference was found in the number of regenerating myofibers displaying centrally located nuclei. On the other hand, we did observe increased collagen content, which denotes fibrosis, in the muscles of rGDF11-treated dystrophic mice.ConclusionsTaken together, our findings indicate no beneficial effect of treating dystrophic mice with rGDF11 and raise caution to a potential harmful effect, as shown by the pro-fibrotic outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0092-8) contains supplementary material, which is available to authorized users.

Low Relative Lean Mass is Associated with Increased Likelihood of Abdominal Aortic Calcification in Community-Dwelling Older Australians.

Age-related loss of skeletal muscle is associated with increased risk of functional limitation and cardiovascular (CV) mortality. In the elderly abdominal aortic calcification (AAC) can increase CV risk by altering aortic properties which may raise blood pressure and increase cardiac workload. This study investigated the association between low muscle mass and AAC in community-dwelling older Australians. Data for this cross-sectional analysis were drawn from a 2010 sub-study of the Melbourne Collaborative Cohort Study in the setting of community-dwelling older adults. Three hundred and twenty-seven participants [mean age=71±6years; mean BMI=28±5kg/m(2); females n=199 (62%)] had body composition determined by dual-energy x-ray absorptiometry (DXA) and AAC determined by radiography. Participants were stratified into tertiles of sex-specific BMI-normalised appendicular lean mass (ALM). Those in the lowest tertile were considered to have low relative muscle mass. Aortic calcification score (ACS) was determined visually as the extent of calcification on the aortic walls between L1 and L4 vertebrae (range: 0-24). Severe AAC was defined as ACS≥6. Prevalence of any AAC was highest in participants with low relative muscle mass (74%) compared to the middle (65%) and upper (53%) tertiles (p trend=0.006). The lower ALM/BMI tertile had increased odds (Odds ratio=2.3; 95% confidence interval: 1.1-4.6; p=0.021) of having any AAC; and having more severe AAC (2.2; 1.2-4.0; p=0.009) independent of CV risk factors, serum calcium and physical activity. AAC is more prevalent and severe in community-dwelling older adults with low relative muscle mass. Maintaining muscle mass could form part of a broader primary prevention strategy in reducing AAC.

Whey protein, amino acids, and vitamin D supplementation with physical activity increases fat-free mass and strength, functionality, and quality of life and decreases inflammation in sarcopenic elderly

AbstractBackground: Interventions to attenuate the adverse effects of age-related loss of skeletal muscle and function include increased physical activity and nutritional supplementation.Objective: This study tested the hypothesis that nutritional supplementation with whey protein (22 g), essential amino acids (10.9 g, including 4 g leucine), and vitamin D [2.5 μg (100 IU)] concurrent with regular, controlled physical activity would increase fat-free mass, strength, physical function, and quality of life, and reduce the risk of malnutrition in sarcopenic elderly persons.Design: A total of 130 sarcopenic elderly people (53 men and 77 women; mean age: 80.3 y) participated in a 12-wk randomized, double-blind, placebo-controlled supplementation trial. All participants concurrently took part in a controlled physical activity program. We examined body composition with dual-energy X-ray absorptiometry, muscle strength with a handgrip dynamometer, and blood biochemical indexes of nutritional and health status, and evaluated global nutritional status, physical function, and quality of life before and after the 12 wk of intervention.Results: Compared with physical activity and placebo, supplementation plus physical activity increased fat-free mass (1.7-kg gain, P < 0.001), relative skeletal muscle mass (P = 0.009), android distribution of fat (P = 0.021), handgrip strength (P = 0.001), standardized summary scores for physical components (P = 0.030), activities of daily living (P = 0.001), mini nutritional assessment (P = 0.003), and insulin-like growth factor I (P = 0.002), and lowered C-reactive protein (P = 0.038).Conclusion: Supplementation with whey protein, essential amino acids, and vitamin D, in conjunction with age-appropriate exercise, not only boosts fat-free mass and strength but also enhances other aspects that contribute to well-being in sarcopenic elderly. This trial was registered at clinicaltrials.gov as NCT02402608.

Implications of skeletal muscle loss for public health nutrition messages: a brief report.

Age-related skeletal muscle loss, sarcopenia, cachexia and wider malnutrition (under nutrition) are complex in aetiology with interaction of clinical, social and economic factors. Weight loss and loss of skeletal muscle mass in older people are associated with increased morbidity and mortality with implications for increasing health and social care costs. There is insufficient evidence to identify the ideal treatment options. However, preventing weight loss and loss of skeletal muscle in older age will be keys to reducing morbidity and mortality. This will require all those coming into contact with older people to identify and address weight loss early, including through diet, improving physical activity and increasing social interaction. Public health messages on diet should, in the main, continue to focus on older people achieving current UK dietary recommendations for their age as visually depicted in the eatwell plate together with associated messages regarding dietary supplements where appropriate.

G.P.202: Characterization of skeletal muscle and heart during aging in rats, and response to formoterol, a selective β2 adrenoceptor agonist, in aged rats

Loss of skeletal muscle function and mass occurs during aging as well as under various disease conditions, such as cancer, COPD, liver disease, and congestive heart failure. Despite the high prevalence of such conditions, no effective treatment for muscle wasting diseases exists. In particular, sarcopenia, under the concept of frailty frequently observed in elderly people, is a geriatric syndrome defined by an excessive reduction in muscle mass and a concurrent decline in physical function, leading to mobility limitations, reduced quality of life, increased risk of falls, fractures and hospitalizations, and ultimately loss of independence. Selective β2 adrenoceptor agonists elicit skeletal muscle hypertrophy associated with increased force producing capacity. Several studies have reported efficacy of β2 adrenoceptor agonists in improving muscle wasting in many animal species and humans. Here, skeletal muscle and heart in aged rats were characterized with regard to mass, function and gene expression changes. Progressive loss of mass and force production capacity in skeletal muscle was observed; in contrast cardiac mass was increased and its function was decreased. In skeletal muscles, these phenotypic changes were associated with dramatic changes in genes known to be involved in atrophy, differentiation and in particular neuromuscular junction. In the heart, gene expression changes indicated pathological remodeling including up-regulation of fetal gene markers. Furthermore, the effect of formoterol on skeletal muscle and heart of aged sarcopenic rats was evaluated. The treatment spared the age-related loss of skeletal muscle mass and force production capacity in rats, while increasing heart weight. Hence, although β2 adrenoceptor agonists might be a potential therapeutic option for treating age-related loss of skeletal muscle, development of skeletal muscle selective agents is awaited since any detrimental cardiac effects may not be tolerated in elderly population.

An ethanolic extract of Artemisia dracunculus L. regulates gene expression of ubiquitin–proteasome system enzymes in skeletal muscle: Potential role in the treatment of sarcopenic obesity

ObjectiveObesity is linked to insulin resistance, a primary component of metabolic syndrome and type 2 diabetes. The problem of obesity-related insulin resistance is compounded when age-related skeletal muscle loss, called sarcopenia, occurs with obesity. Skeletal muscle loss results from elevated levels of protein degradation and prevention of obesity-related sarcopenic muscle loss will depend on strategies that target pathways involved in protein degradation. An extract from Artemisia dracunculus, termed PMI 5011, improves insulin signaling and increases skeletal muscle myofiber size in a rodent model of obesity-related insulin resistance. The aim of this study was to examine the effect of PMI 5011 on the ubiquitin–proteasome system, a central regulator of muscle protein degradation. MethodsGastrocnemius and vastus lateralis skeletal muscle was obtained from KK-Ay obese diabetic mice fed a control or 1% (w/w) PMI 5011-supplemented diet. Regulation of genes encoding enzymes of the ubiquitin–proteasome system was determined using real-time quantitative reverse transcriptase polymerase chain reaction. ResultsAlthough MuRF-1 ubiquitin ligase gene expression is consistently down-regulated in skeletal muscle, atrogin-1, Fbxo40, and Traf6 expression is differentially regulated by PMI 5011. Genes encoding other enzymes of the ubiquitin–proteasome system ranging from ubiquitin to ubiquitin-specific proteases are also regulated by PMI 5011. Additionally, expression of the gene encoding the microtubule-associated protein-1 light chain 3 (LC3), a ubiquitin-like protein pivotal to autophagy-mediated protein degradation, is down-regulated by PMI 5011 in the vastus lateralis. ConclusionPMI 5011 alters the gene expression of ubiquitin–proteasome system enzymes that are essential regulators of skeletal muscle mass. This suggests that PMI 5011 has therapeutic potential in the treatment of obesity-linked sarcopenia by regulating ubiquitin–proteasome-mediated protein degradation.

Nutritional influences on age-related skeletal muscle loss

Age-related muscle loss impacts on whole-body metabolism and leads to frailty and sarcopenia, which are risk factors for fractures and mortality. Although nutrients are integral to muscle metabolism the relationship between nutrition and muscle loss has only been extensively investigated for protein and amino acids. The objective of the present paper is to describe other aspects of nutrition and their association with skeletal muscle mass. Mechanisms for muscle loss relate to imbalance in protein turnover with a number of anabolic pathways of which the mechanistic TOR pathway and the IGF-1-Akt-FoxO pathways are the most characterised. In terms of catabolism the ubiquitin proteasome system, apoptosis, autophagy, inflammation, oxidation and insulin resistance are among the major mechanisms proposed. The limited research associating vitamin D, alcohol, dietary acid-base load, dietary fat and anti-oxidant nutrients with age-related muscle loss is described. Vitamin D may be protective for muscle loss; a more alkalinogenic diet and diets higher in the anti-oxidant nutrients vitamin C and vitamin E may also prevent muscle loss. Although present recommendations for prevention of sarcopenia focus on protein, and to some extent on vitamin D, other aspects of the diet including fruits and vegetables should be considered. Clearly, more research into other aspects of nutrition and their role in prevention of muscle loss is required.

Weight loss in obese adults 65 years and older: A review of the controversy

Obesity in older adults is ubiquitous in many developed countries and is related to various negative health outcomes, making it an important public health target for intervention. However, treatment approaches for obesity in older adults remain controversial due to concerns surrounding the difficulty of behavior change with advancing age, exacerbating the age-related loss of skeletal muscle and bone, and the feasibility of long-term weight maintenance and related health consequences. This review serves to systematically examine the evidence regarding weight loss interventions with a focus on obese (body mass index 30kg/m2 and above) older adults (aged 65years and older) and some proposed mechanisms associated with exercise and caloric restriction (lifestyle intervention). Our findings indicate that healthy weight loss in this age group can be achieved through lifestyle interventions of up to a one-year period. Most interventions reviewed reported a loss of lean body mass and bone mineral density with weight loss. Paradoxically muscle quality and physical function improved. Inflammatory molecules and metabolic markers also improved, although the independent and additive effects of exercise and weight loss on these pathways are poorly understood. Using our review inclusion criteria, only one small pilot study investigating long-term weight maintenance and associated health implications was found in the literature. Future research on lifestyle interventions for obese older adults should address the loss of bone and lean body mass, inflammatory mechanisms, and include sufficient follow-up to assess long-term weight maintenance and health outcomes.

The Aging Phenomenon, Related with DNA Damage, MMR Deficiency and Oxidative Stress, Has Different Outcomes in Two Species of the Order Chiroptera

Divergent Roles for 12/15-Lipoxygenase and 5Lipoxygenase Lipid Metabolic Pathways in Neurogenic Muscle Atrophy Arunabh Bhattacharya, Ryan Hamilton, Carmen Rios, Amanda L Jernigan, Yiqiang Zhang, Marian Sabia, Md M Rahman, Yan Li, Wenbo Qi, and Holly Van Remmen University of Texas Health Science Center at San Antonio, GRECC, South Texas Veterans Health Care System, San Antonio Aging is associated with progressive decline in muscle mass and function which significantly impacts the quality of life in the elderly population. Studies by our group and others have shown that decline in neuromuscular junction integrity (i.e. loss of innervation) during aging plays a causative role in age-related loss of muscle mass and function. However, little is known about the pathways and/or mediators that induce muscle atrophy during age-related loss of skeletal muscle during denervation. We previously showed that muscle atrophy during aging and surgical denervation is associated with increase in the expression of cytosolic phospholipase A2, the rate limiting step for release of arachidonic acid from membranes which then acts as a substrate for lipid metabolic pathways catalyzed by 12/15-lipoxygenase (12/15-LO), 5-lipoxygenase (5-LO) and cyclooxygenase and leads to the generation of bioactive lipid metabolites that are important mediators of inflammation and/or oxidative stress. In this study, we report that the expression and activity of 5and 12/15-LO pathways are significantly elevated in atrophied muscles from denervated mice. While genetic ablation/pharmacological inhibition of 12/15-LO confers protection against denervationinduced muscle atrophy, genetic ablation/pharmacological inhibition of 5-LO tends to increase muscle atrophy. We find that the activation of 12/15-LO pathway during denervation-atrophy increases NADPH oxidase mediated oxidative stress which leads to oxidative damage to lipids and proteins and increased proteolytic degradation by the ubiquitin-proteasome pathway. These findings reveal for the first time divergent roles for 5-LO and 12/15-LO lipid signaling pathways in muscle atrophy during loss of innervation.

Sarcopenia and Age-Related Endocrine Function

Sarcopenia, the age-related loss of skeletal muscle, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, and an increased risk of fall-related injuries. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, numerous targets exist for drug discovery. In this paper, we summarize the current understanding of the endocrine contribution to sarcopenia and provide an update on hormonal intervention to try to improve endocrine defects. Myostatin inhibition seems to be the most interesting strategy for attenuating sarcopenia other than resistance training with amino acid supplementation. Testosterone supplementation in large amounts and at low frequency improves muscle defects with aging but has several side effects. Although IGF-I is a potent regulator of muscle mass, its therapeutic use has not had a positive effect probably due to local IGF-I resistance. Treatment with ghrelin may ameliorate the muscle atrophy elicited by age-dependent decreases in growth hormone. Ghrelin is an interesting candidate because it is orally active, avoiding the need for injections. A more comprehensive knowledge of vitamin-D-related mechanisms is needed to utilize this nutrient to prevent sarcopenia.

Comparison of ultrasound-measured age-related, site-specific muscle loss between healthy Japanese and German men

The purpose of this study was to compare the age-related muscle loss in both the appendicular and trunk regions in 207 Japanese and 111 German men aged 20-62 years. Ultrasound-measured muscle thickness (MTH) was taken at eight sites from the anterior and posterior aspects of the body, and the MTH was expressed in terms relative to limb length (MTH/L) or standing height (MTH/Ht). In both the Japanese and Germans, age was correlated with quadriceps MTH (Japanese, r = -0·347; Germans, r = -0·292; both P<0·01) and abdomen MTH (Japanese, r = -0·300, P<0·01; Germans, r = -0·232; P<0·05). On the other hand, hamstring MTH was correlated with age in the Japanese (r = -0·188, P<0·01), but not in the Germans (r = 0·100). There were no significant correlations between age and other limb (i.e. triceps surae MTH/L, Japanese, r = 0·04; Germans, r = 0·05) and trunk sites (subscapula MTH/Ht, Japanese, r = -0·09; Germans, r = -0·02). In conclusion, age-related skeletal muscle loss was strongly observed in the quadriceps and abdominal sites in both the Japanese and German men, although the rate of regular physical activity was different between the two groups.

Association of vigorous physical activity with age-related, site-specific loss of thigh muscle in women: the HIREGASAKI study

body, constitutes approximately 40% of fat-free body mass in young adults1 but decreases with advancing age, especially after the fifth decade of life.2 These age-related changes lead to a decline of strength and power, a decrease in physical performance, and disability.3 Because the population of elderly people is growing in most countries, including Japan, the agerelated loss of skeletal muscle mass is likely to have a severe economic impact on the healthcare system. Age-related loss of skeletal muscle mass (Sarcopenia) has been studied extensively by evaluating muscle volume, muscle cross-sectional area (CSA), and anatomical muscle thickness (MTH).4 Recently, Abe and colleagues demonstrated that age is associated with site-specific loss of skeletal muscle mass in Japanese men and women5,6 and in German men7. Interestingly, in the anterior and posterior regions of the thigh, age-related muscle loss was observed in the quadriceps but not in the hamstrings and adductors.8 The etiology of sitespecific sarcopenia is multifactorial and complex. Several factors have been implicated such as declining anabolic hormone concentrations, nutritional deficiencies, chronic inflammation, and insulin resistance.5,7 Decreased physical activity levels that occur with aging also contribute to sarcopenia. It is well established that hormonal receptors for mRNA and transcriptional activity are increased8 and that there is reduced insulin resistance9 in exercising muscles following an acute bout of exercise for sedentary individuals. There are therefore many important interrelationships between physical activity levels and other etiologic factors associated with health and aging that may contribute in varying degrees to the age-related loss of skeletal muscle mass in older populations. More recently, we examined the effect of habitual physical activity on age-related loss of skeletal muscle and found that there is site-specific loss in both active (more than once a week) and inactive old women.10 In that study, the subjects were classified into active and inactive groups based on their self-reported habitual physical activity. The effect of exercise intensity and duration of daily physical activities on site-specific loss of thigh muscle is unknown. However, muscle mass and strength losses associated with increasing age

Age‐related anabolic resistance after endurance‐type exercise in healthy humans

Age-related skeletal muscle loss is thought to stem from suboptimal nutrition and resistance to anabolic stimuli. Impaired microcirculatory (nutritive) blood flow may contribute to anabolic resistance by reducing delivery of amino acids to skeletal muscle. In this study, we employed contrast-enhanced ultrasound, microdialysis sampling of skeletal muscle interstitium, and stable isotope methodology, to assess hemodynamic and metabolic responses of older individuals to endurance type (walking) exercise during controlled amino acid provision. We hypothesized that older individuals would exhibit reduced microcirculatory blood flow, interstitial amino acid concentrations, and amino acid transport when compared with younger controls. We report for the first time that aging induces anabolic resistance following endurance exercise, manifested as reduced (by ∼40%) efficiency of muscle protein synthesis. Despite lower (by ∼40-45%) microcirculatory flow in the older than in the younger participants, circulating and interstitial amino acid concentrations and phenylalanine transport into skeletal muscle were all equal or higher in older individuals than in the young, comprehensively refuting our hypothesis that amino acid availability limits postexercise anabolism in older individuals. Our data point to alternative mediators of age-related anabolic resistance and importantly suggest correction of these impairments may reduce requirements for, and increase the efficacy of, dietary protein in older individuals.

Regulation of Muscle Atrophy: Wasting Away from the Outside In

Whereas it is clear that periods of detraining, disuse, injury and aging are marked by losses in skeletal muscle mass and function, the emerging literature suggests that there are unique molecular signaling alterations depending on the perturbation. Understanding the phenotypical adaptations in skeletal muscle and factors that are thought to promote or inhibit genes involved in the atrophy program will elucidate how the muscular system responds to decreases in activity. Recent advances in the discipline have identified specific and innovative methods to promote skeletal muscle hypertrophy including gene therapy, pharmacological, and nutritional interventions. The same success has not been met concerning attenuating skeletal muscle atrophy. If novel approaches are to be implemented in humans to mitigate disuse- and age-related skeletal muscle loss, it is imperative that we evaluate critical regulators of skeletal muscle atrophy from a system to the cellular level. The symposium "Regulation of Muscle Atrophy: Wasting Away from the Outside In" was presented at the ACSM Annual Meeting in Indianapolis on May 29, 2008, to provide an overview of the skeletal muscle atrophy literature and our current understanding of the atrophy program from the whole system to the molecular level. In addition, this symposium addressed the feasibility of intervening with specific countermeasures to attenuate atrophy. This introduction identifies the scope of the symposium, which evaluates our current understanding of the atrophy program and how this information can facilitate the development of effective countermeasures.

An Analysis of the Dietary Protein Intake of Hospitalized Elders

Age related skeletal muscle loss results in reduction of strength and functional capabilities. During hospitalization physical activity is restricted, muscle loss is accelerated, and dietary protein intake becomes increasingly important as it represents one of the few means of upregulating muscle protein synthesis. The purpose of this study was to quantify the protein intake of hospitalized elderly patients in the ACE unit of a university hospital. Hospital meal plan data were entered into a nutritional software program and analyzed for nutrient content. The proportion of a single representative meal consumed was recorded for thirteen patients (77.5 ± 1.8 yrs). The hospital lunch meal provided 41.7 ± 2.0g of protein. However, patients consumed only 34.6% of the protein provided (14.4 ± 3.1g). Ten of the 13 subjects consumed less than 20g of protein (0.19 ± 0.04g/kg). The primary reason for low protein intake was an inadequate consumption of the animal protein menu item. In 6 of the 13 subjects, more than 50% of the protein ingested was attributed to the dessert item. Despite encouragement from dietary and medical staff, actual consumption was less than one‐third of the RDA for protein. If protein intake cannot be increased via provision of high quality protein‐rich foods, complementary nutritional strategies (e.g. amino acid supplementation) should be considered.

Muscle precursor cells isolated from aged rats exhibit an increased tumor necrosis factor‐α response

Improving muscle precursor cell (MPC, muscle-specific stem cells) function during aging has been implicated as a key therapeutic target for improving age-related skeletal muscle loss. MPC dysfunction during aging can be attributed to both the aging MPC population and the changing environment in skeletal muscle. Previous reports have identified elevated levels of tumor necrosis factor- alpha (TNF- alpha ) in aging, both circulating and locally in skeletal muscle. The purpose of the present study was to determine if age-related differences exist between TNF- alpha -induced nuclear factor-kappa B (NF- kappaB) activation and expression of apoptotic gene targets. MPCs isolated from 32-month-old animals exhibited an increased NF- kappaB activation in response to 1, 5, and 20 ng mL(-1) TNF- alpha, compared to MPCs isolated from 3-month-old animals. No age differences were observed in the rapid canonical signaling events leading to NF- kappaB activation or in the increase in mRNA levels for TNF receptor 1, TNF receptor 2, TNF receptorassociated factor 2 (TRAF2), or Fas (CD95) observed after 2 h of TNF- alpha stimulation. Interestingly, mRNA levels for TRAF2 and the cell death-inducing receptor, Fas (CD95), were persistently upregulated in response to 24 h TNF- alpha treatment in MPCs isolated from 32-month-old animals, compared to 3-month-old animals. Our data indicate that age-related differences may exist in the regulatory mechanisms responsible for NF- kappaB inactivation, which may have an effect on TNF- alpha-induced apoptotic signaling. These findings improve our understanding of the interaction between aged MPCs and the changing environment associated with age, which is critical for the development of potential clinical interventions aimed at improving MPC function with age.