Current Nutritional and Pharmacological Approaches for Attenuating Sarcopenia.

Sarcopenia is characterized by a gradual slowing of movement due to loss of muscle mass and quality, decreased power and strength, increased risk of injury from falls, and often weakness. This review will focus on recent research trends in nutritional and pharmacological approaches to controlling sarcopenia. Because nutritional studies in humans are fairly limited, this paper includes many results from nutritional studies in mammals. The combination of resistance training with supplements containing amino acids is the gold standard for preventing sarcopenia. Amino acid (HMB) supplementation alone has no significant effect on muscle strength or muscle mass in sarcopenia, but the combination of HMB and exercise (whole body vibration stimulation) is likely to be effective. Tea catechins, soy isoflavones, and ursolic acid are interesting candidates for reducing sarcopenia, but both more detailed basic research on this treatment and clinical studies in humans are needed. Vitamin D supplementation has been shown not to improve sarcopenia in elderly individuals who are not vitamin D-deficient. Myostatin inhibitory drugs have been tried in many neuromuscular diseases, but increases in muscle mass and strength are less likely to be expected. Validation of myostatin inhibitory antibodies in patients with sarcopenia has been positive, but excessive expectations are not warranted.

Interactions between monthly training volume, frequency and running distance per workout on marathon time.

PURPOSE: This study attempted to clarify the relationships between marathon time and monthly training volume, training frequency and the longest (LRD) or average running distance per workout (ARD), as well as their interactions. METHODS: Male recreational runners (n = 587) participating in the Hokkaido Marathon 2017 completed a questionnaire before the race; of these, 494 finished the race. We assessed age, running career, body height, body weight, body mass index (BMI), monthly training volume, training frequency, the LRD and the ARD. These indicators were each divided into 4 or 5 homogeneous subgroups to determine whether the other indicators in each subgroup predicted marathon time. RESULTS: In the training frequency subgroups, there were significant correlations between monthly training volume, the LRD or the ARD and marathon time, except for the subgroup that trained 2 times per week or less; in this subgroup, the relationship between the ARD and marathon time was not significant. In all monthly training volume subgroups, there were no significant relationships between training frequency, the LRD or the ARD and marathon time. In the ≥ 21 km LRD and ≥ 10 km ARD subgroups, there were significant correlations between monthly training volume and marathon time (all P < 0.01); these correlations were not significant in the 1-20 km LRD and < 10 km ARD subgroups. CONCLUSION: These results indicate that monthly training volume is the most important factor in predicting marathon time and that the influence of monthly training volume is only significant if the running distance per workout exceeded a certain level.

Pathophysiology of cachexia and characteristics of dysphagia in chronic diseases.

Cachexia is a condition characterized by skeletal muscle loss, weight loss, and anorexia. It is a complication of many diseases, not only cancer, and is characterized by chronic systemic inflammation. Cachexia and sarcopenia share common factors. The various symptoms observed in cachexia may be caused by multiple factors and inflammatory cytokines secreted by a tumor. Essentially, sarcopenia develops with aging, but it can occur at younger ages in the presence of cachexia, malnutrition, and disuse syndrome. In a recent study, dysphagia was found to be closely associated with malnutrition and sarcopenia. Factors specific to chronic diseases may influence the clinical outcome of dysphagia. Elderly people frequently exhibit dysphagia, but no research has been reported on whether cachexia is directly linked with dysphagia. Dysphagia is an important clinical problem, leading to aspiration pneumonia, suffocation, dehydration, malnutrition, and death. In addition to treating the patient, the degree of dysphagia needs to be accurately assessed. This review focuses on the pathogenesis of cachexia and the prevalence of dysphagia-related diseases, methods of assessment, and their impact on clinical outcomes.

Association of Oral Function and Dysphagia with Frailty and Sarcopenia in Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis.

Studies investigating the associations of oral function and dysphagia with frailty and sarcopenia in community-dwelling older adults are increasing; however, they have not been systematically summarized. We conducted a systematic review to investigate these associations. We searched electronic databases and synthesized relevant data using conventional (frequentist-style) and Bayesian meta-analyses. Twenty-four studies were found to be eligible for our review, including 20 cross-sectional and four prospective cohort studies. Older adults with frailty or sarcopenia had lower tongue pressure, according to the results of conventional meta-analysis (mean difference [95% confidence interval or credible interval]: -6.80 kPa [-10.22 to -3.38] for frailty and -5.40 kPa [-6.62 to -4.17] for sarcopenia) and Bayesian meta-analysis (-6.90 kPa [-9.0 to -4.8] for frailty, -5.35 kPa [-6.78 to -3.89] for sarcopenia). People with frailty had a higher odds ratio (OR) for dysphagia according to the results of conventional meta-analysis (3.99 [2.17 to 7.32]) and Bayesian meta-analysis (1.38 [0.77 to 1.98]). However, the results were inconclusive for people with sarcopenia. A prospective association could not be determined because of the lack of information and the limited number of studies. Decreased oral function and dysphagia can be important characteristics of frailty and sarcopenia in community-dwelling older adults.

Secreted protein acidic and rich in cysteine (SPARC) improves glucose tolerance via AMP-activated protein kinase activation.

During exercise, skeletal muscles release cytokines, peptides, and metabolites that exert autocrine, paracrine, or endocrine effects on glucose homeostasis. In this study, we investigated the effects of secreted protein acidic and rich in cysteine (SPARC), an exercise-responsive myokine, on glucose metabolism in human and mouse skeletal muscle. SPARC-knockout mice showed impaired systemic metabolism and reduced phosphorylation of AMPK and protein kinase B in skeletal muscle. Treatment of SPARC-knockout mice with recombinant SPARC improved glucose tolerance and concomitantly activated AMPK in skeletal muscle. These effects were dependent on AMPK-γ3 because SPARC treatment enhanced skeletal muscle glucose uptake in wild-type mice but not in AMPK-γ3-knockout mice. SPARC strongly interacted with the voltage-dependent calcium channel, and inhibition of calcium-dependent signaling prevented SPARC-induced AMPK phosphorylation in human and mouse myotubes. Finally, chronic SPARC treatment improved systemic glucose tolerance and AMPK signaling in skeletal muscle of high-fat diet-induced obese mice, highlighting the efficacy of SPARC treatment in the management of metabolic diseases. Thus, our findings suggest that SPARC treatment mimics the effects of exercise on glucose tolerance by enhancing AMPK-dependent glucose uptake in skeletal muscle.-Aoi, W., Hirano, N., Lassiter, D. G., Björnholm, M., Chibalin, A. V., Sakuma, K., Tanimura, Y., Mizushima, K., Takagi, T., Naito, Y., Zierath, J. R., Krook, A. Secreted protein acidic and rich in cysteine (SPARC) improves glucose tolerance via AMP-activated protein kinase activation.

The influence of isoflavone for denervation-induced muscle atrophy.

PURPOSE: Decrease in activity stress induces skeletal muscle atrophy. A previous study showed that treatment with a high level (20%) of isoflavone inhibits muscle atrophy after short-term denervation (at 4 days) in mice. The present study was designed to elucidate whether the dietary isoflavone aglycone (AglyMax) at a 0.6% prevents denervation-mediated muscle atrophy, based on the modulation of atrogin-1- or apoptosis-dependent signaling. METHODS: Mice were fed either a normal diet or 0.6% AglyMax diet. One week later, the right sciatic nerve was cut. The wet weight, mean fiber area, amount of atrogin-1 and cleaved caspase-3 proteins, and the percentages of apoptotic nuclei were examined in the gastrocnemius muscle at 14 days after denervation. RESULTS: The 0.6% AglyMax diet significantly attenuated denervation-induced decreases in fiber atrophy but not the muscle wet weight. In addition, dietary isoflavone suppressed the denervation-induced apoptosis in spite of there being no significant changes in the amount of cleaved caspase-3 protein. In contrast, the 0.6% AglyMax diet did not significantly modulate the protein expression of atrogin-1 in the denervated muscle of mice. CONCLUSIONS: The isoflavone aglycone (AglyMax) at a 0.6% significantly would modulate muscle atrophy after denervation in mice, probably due to the decrease in apoptosis-dependent signaling.

Drugs of Muscle Wasting and Their Therapeutic Targets.

Muscle wasting and weakness such as cachexia, atrophy, and sarcopenia are characterized by marked decreases in the protein content, myonuclear number, muscle fiber size, and muscle strength. This chapter focuses on the recent advances of pharmacological approach for attenuating muscle wasting.A myostatin-inhibiting approach is very intriguing to prevent sarcopenia but not muscular dystrophy in humans. Supplementation with ghrelin is also an important candidate to combat sarcopenia as well as cachexia. Treatment with soy isoflavone, trichostatin A (TSA), and cyclooxygenase 2 (Cox2) inhibitors seems to be effective modulators attenuating muscle wasting, although further systematic research is needed on this treatment in particular concerning side effects.

Resveratrol attenuates denervation-induced muscle atrophy due to the blockade of atrogin-1 and p62 accumulation.

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.

Recent advances in pharmacological, hormonal, and nutritional intervention for sarcopenia.

Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and often frailty. This review focuses on the recent advances of pharmacological, hormonal, and nutritional approaches for attenuating sarcopenia. The article is composed of the data reported in many basic and some clinical studies for mammalian muscles. Resistance training combined with amino acid-containing supplements is the gold standard to prevent sarcopenia. Supplementation with proteins (amino acids) only did not influence sarcopenic symptoms. A myostatin-inhibiting strategy is the most important candidate to prevent sarcopenia in humans. Milder caloric restriction (CR, 15-25%) would also be effective for age-related muscle atrophy in humans. Supplementation with ursolic acid and ghrelin is an intriguing candidate to combat sarcopenia, although further systematic and fundamental research is needed on this treatment.

Molecular mechanism of sarcopenia and cachexia: recent research advances.

Skeletal muscle provides a fundamental basis for human function, enabling locomotion and respiration. Muscle loss occurs as a consequence of several chronic diseases (cachexia) and normal aging (sarcopenia). Although many negative regulators (atrogin-1, muscle ring finger-1, nuclear factor-kappaB (NF-κB), myostatin, etc.) have been proposed to enhance protein degradation during both sarcopenia and cachexia, the adaptation of these mediators markedly differs within both conditions. Sarcopenia and cachectic muscles have been demonstrated to be abundant in myostatin-linked molecules. The ubiquitin-proteasome system (UPS) is activated during rapid atrophy model (cancer cachexia), but few mediators of the UPS change during sarcopenia. NF-κB signaling is activated in cachectic, but not in sarcopenic, muscle. Recent studies have indicated the age-related defect of autophagy signaling in skeletal muscle, whereas autophagic activation occurs in cachectic muscle. This review provides recent research advances dealing with molecular mediators modulating muscle mass in both sarcopenia and cachexia.

p62/SQSTM1 but not LC3 is accumulated in sarcopenic muscle of mice.

AIM: We investigated the pathway of autophagy signaling linked to sarcopenia of mice. METHODS: Young adult (3-month) and aged (24- month) C57BL/6J mice were used. Using real-time PCR, Western blotting, and immunohistochemical microscopy, we evaluated the amounts of p62/SQSTM1, LC3, and Beclin-1 in the quadriceps muscle change with aging in mice. RESULTS: Marked fiber atrophy (30%) and many fibers with central nuclei were observed in the aged mice. Western blotting using homogenate of the cytosolic fraction clearly showed that the amounts of p62/SQSTM1 and Beclin-1 proteins were significantly increased in the aged skeletal muscle. The amounts of these proteins in both nuclear and membrane fractions did not change significantly with age. Immunofluorescence labeling indicated that aged mice more frequently possessed p62/SQSTM1-positive fibers in the cytosol in quadriceps muscle than young ones (aged: 14% vs. young: 1%). In aged muscle, p62/SQSTM1-positive fibers were significantly smaller than the surrounding p62/SQSTM1-negative fibers. Aging did not elicit significant changes in the mRNA levels of p62/SQSTM1 and Beclin-1, but decreased LC3 mRNA level. In aged muscle, the location of p62/SQSTM1 immunoreactivity was similar to that of Beclin-1 protein, but not LC3. CONCLUSION: Sarcopenia in mice appears to include a marked defect of autophagy signaling.

Current understanding of sarcopenia: possible candidates modulating muscle mass.

The world's elderly population is expanding rapidly, and we are now faced with the significant challenge of maintaining or improving physical activity, independence, and quality of life in the elderly. Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Muscle loss has been linked with several proteolytic systems, including the ubuiquitin-proteasome, lysosome-autophagy, and tumor necrosis factor (TNF)-α/nuclear factor-kappaB (NF-κB) systems. Although many factors are considered to regulate age-dependent muscle loss, this gentle atrophy is not affected by factors known to enhance rapid atrophy (denervation, hindlimb suspension, etc.). In addition, defects in Akt-mammalian target of rapamycin (mTOR) and serum response factor (SRF)-dependent signaling have been found in sarcopenic muscle. Intriguingly, more recent studies indicated an apparent functional defect in autophagy- and myostatin-dependent signaling in sarcopenic muscle. In this review, we summarize the current understanding of the adaptation of many regulators in sarcopenia.

The intriguing regulators of muscle mass in sarcopenia and muscular dystrophy.

Recent advances in our understanding of the biology of muscle have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle mass and increased intramuscular fibrosis occur in both sarcopenia and muscular dystrophy. Several regulators (mammalian target of rapamycin, serum response factor, atrogin-1, myostatin, etc.) seem to modulate protein synthesis and degradation or transcription of muscle-specific genes during both sarcopenia and muscular dystrophy. This review provides an overview of the adaptive changes in several regulators of muscle mass in both sarcopenia and muscular dystrophy.

Rehabilitation nutrition for sarcopenia with disability: a combination of both rehabilitation and nutrition care management.

Malnutrition and sarcopenia often occur in rehabilitation settings. The prevalence of malnutrition and sarcopenia in older patients undergoing rehabilitation is 49-67 % and 40-46.5 %, respectively. Malnutrition and sarcopenia are associated with poorer rehabilitation outcome and physical function. Therefore, a combination of both rehabilitation and nutrition care management may improve outcome in disabled elderly with malnutrition and sarcopenia. The concept of rehabilitation nutrition as a combination of both rehabilitation and nutrition care management and the International Classification of Functioning, Disability and Health guidelines are used to evaluate nutrition status and to maximize functionality in the elderly and other people with disability. Assessment of the multifactorial causes of primary and secondary sarcopenia is important because rehabilitation nutrition for sarcopenia differs depending on its etiology. Treatment of age-related sarcopenia should include resistance training and dietary supplements of amino acids. Therapy for activity-related sarcopenia includes reduced bed rest time and early mobilization and physical activity. Treatment for disease-related sarcopenia requires therapies for advanced organ failure, inflammatory disease, malignancy, or endocrine disease, while therapy for nutrition-related sarcopenia involves appropriate nutrition management to increase muscle mass. Because primary and secondary sarcopenia often coexist in people with disability, the concept of rehabilitation nutrition is useful for their treatment. Stroke, hip fracture, and hospital-associated deconditioning are major causes of disability, and inpatients of rehabilitation facilities often have malnutrition and sarcopenia. We review the concept of rehabilitation nutrition, the rehabilitation nutrition options for stroke, hip fracture, hospital-associated deconditioning, sarcopenic dysphagia, and then evaluate the amount of research interest in rehabilitation nutrition.

Vitamin D signaling in myogenesis: potential for treatment of sarcopenia.

Muscle mass and strength progressively decrease with age, which results in a condition known as sarcopenia. Sarcopenia would lead to physical disability, poor quality of life, and death. Therefore, much is expected of an effective intervention for sarcopenia. Epidemiologic, clinical, and laboratory evidence suggest an effect of vitamin D on muscle function. However, the precise molecular and cellular mechanisms remain to be elucidated. Recent studies suggest that vitamin D receptor (VDR) might be expressed in muscle fibers and vitamin D signaling via VDR plays a role in the regulation of myoblast proliferation and differentiation. Understanding how vitamin D signaling contributes to myogenesis will provide a valuable insight into an effective nutritional strategy to moderate sarcopenia. Here we will summarize the current knowledge about the effect of vitamin D on skeletal muscle and myogenic cells and discuss the potential for treatment of sarcopenia.

Does regulation of skeletal muscle function involve circulating microRNAs?

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation. Recently, growing evidence has shown that miRNAs are taken in by intracellular exosomes, secreted into circulation, and taken up by other cells. Circulating levels of several miRNAs are changed in diseases such as cancer, diabetes, and cardiovascular diseases; therefore, they are suggested to regulate functions of the recipient cells by modulating protein expression. Circulating miRNAs (c-miRNAs) may also modulate skeletal muscle function in physiological and pathological conditions. It has been suggested that acute and chronic exercise transiently or adaptively changes the level of c-miRNAs, thus post-transcriptionally regulating proteins associated with energy metabolism, myogenesis, and angiogenesis. Circulating levels of several miRNAs that are enriched in muscle are altered in muscle disorders and may be involved in their development and progression. In addition, such c-miRNAs may be useful as biomarkers to determine various interactions between tissues and also to reflect athletic performance, physical fatigue, incidence risk, and development of diseases.

Comprehensive approach to sarcopenia treatment.

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life, and death. Primary sarcopenia is considered to be age-related when no other cause is evident, other than ageing itself. Secondary sarcopenia should be considered when one or more other causes are evident, such as activity-, disease-, or nutrition-related sarcopenia. In this narrative review that focused on human studies, we summarize the pharmaceutical therapies (testosterone, dehydroepiandrosterone, estrogen, growth hormone, ghrelin, vitamin D, angiotensin converting enzyme inhibitor, and eicosapentaenoic acid) and nonpharmaceutical therapies (resistance training, protein and amino acid supplementation, and non-smoking) for counteracting primary sarcopenia. Testosterone and growth hormone improve muscle mass and muscle strength, but have several side effects. Although there are some intriguing pharmaceutical therapies to combat sarcopenia, resistance training combined with supplements containing amino acids are the most effective for preventing and treating age-related muscle wasting and weakness. The etiology of sarcopenia in the elderly is multi-factorial. Patients with disuse syndrome and deconditioning often complicate the diagnosis, of not only activity-related sarcopenia, but also age-, disease-, and nutrition-related sarcopenia. In these cases a comprehensive approach to sarcopenia treatment should include pharmaceutical therapies for age-related sarcopenia and comorbid chronic diseases, resistance training, early ambulation, nutrition management, protein and amino acid supplementation, and non-smoking. The effect of pharmaceutical therapies for sarcopenia can be enhanced by this comprehensive approach. Future research on pharmaceutical therapies for counteracting sarcopenia should consider non-pharmaceutical therapies and also the causes of sarcopenia.

The potential role of sirtuins regarding the effects of exercise on aging- related diseases.

Habitual physical activity and exercise are associated with the mortality rate and significantly contribute to the prevention and/or amelioration of aging-related diseases including metabolic disorders, atherosclerosis, cancer, and dementia. Sirtuins are NAD+-dependent histone deacetylases that have emerged as key regulators of many functions including metabolism, cell growth and apoptosis, as well as control of the aging process. Recent studies have demonstrated that some types of exercise affect the expression and activity of sirtuins in several tissues. This review focuses on the effects of exercise on sirtuins and also their putative role with regard to the effects of exercise on preventing aging- related diseases.

Sarcopenic obesity and endocrinal adaptation with age.

In normal aging, changes in the body composition occur that result in a shift toward decreased muscle mass and increased fat mass. The loss of muscle mass that occurs with aging is termed sarcopenia and is an important cause of frailty, disability, and loss of independence in older adults. Age-related changes in the body composition as well as the increased prevalence of obesity determine a combination of excess weight and reduced muscle mass or strength, recently defined as sarcopenic obesity. Weight gain increases total/abdominal fat, which, in turn, elicits inflammation and fatty infiltration in muscle. Sarcopenic obesity appears to be linked with the upregulation of TNF-α, interleukin (IL)-6, leptin, and myostatin and the downregulation of adiponectin and IL-15. Multiple combined exercise and mild caloric restriction markedly attenuate the symptoms of sarcopenic obesity. Intriguingly, the inhibition of myostatin induced by gene manipulation or neutralizing antibody ameliorates sarcopenic obesity via increased skeletal muscle mass and improved glucose homeostasis. In this review, we describe the possible influence of endocrinal changes with age on sarcopenic obesity.