Regulation Of Muscle Protein Metabolism Research Articles

Sarcopenia: no consensus, no diagnostic criteria, and no approved indication-How did we get here?

In addition to the role of skeletal muscle in movement and locomotion, muscle plays a critical role in a broad array of metabolic processes that can contribute to improved health or risk of disease. The age-associated loss of muscle has been termed sarcopenia. The muscle is the primary site of insulin-stimulated glucose disposal and the largest component of basal metabolic rate, directly and indirectly affects bone density, produces myokines with pleiotropic effect on muscle and other tissues including the brain, and stores essential amino acids essential for the maintenance of protein synthesis during periods of reduced food intake and stress. As such, not surprisingly deterioration of skeletal muscle health, typically operationalized as decline of muscle mass and muscle strength is both a powerful risk factor and main consequence of chronic diseases, disability, and loss of independence, and it is one of the strongest risk factors for mortality. However, skeletal muscle remains one of the most plastic of all tissues, with rapid changes in rates of protein synthesis and degradation in response to physical activity and inactivity, inflammation, and nutritional and hormonal status. This has made the development of pharmacological therapies to increase muscle mass (or prevent loss), an important goal for decades. However, while remarkable advances in the understanding of molecular and cellular regulation of muscle protein metabolism have occurred recently, there are no approved drugs for the treatment of sarcopenia, the loss of skeletal muscle affecting millions of older people. The goal of this paper is to describe the possible reasons for the lack of new and effective pharmacotherapies to treat one of the most important risk factors for age-associated disease and loss of independence.

Water Extract of Lotus Leaf Alleviates Dexamethasone-Induced Muscle Atrophy via Regulating Protein Metabolism-Related Pathways in Mice.

Muscle atrophy is an abnormal condition characterized by loss of skeletal muscle mass and function and is primarily caused by injury, malnutrition, various diseases, and aging. Leaf of lotus (Nelumbo nucifera Gaertn), which has been used for medicinal purposes, contains various active ingredients, including polyphenols, and is reported to exert an antioxidant effect. In this study, we investigated the effect of water extract of lotus leaf (LL) on muscle atrophy and the underlying molecular mechanisms of action. Amounts of 100, 200, or 300 mg/kg/day LL were administered to dexamethasone (DEX)-induced muscle atrophy mice for 4 weeks. Micro-computed tomography (CT) analysis revealed that the intake of LL significantly increased calf muscle volume, surface area, and density in DEX-induced muscle atrophy mice. Administration of LL recovered moving distance, grip strength, ATP production, and body weight, which were decreased by DEX. In addition, muscle damage caused by DEX was also improved by LL. LL reduced the protein catabolic pathway by suppressing gene expression of muscle atrophy F-Box (MAFbx; atrogin-1), muscle RING finger 1 (MuRF1), and forkhead box O (FoxO)3a, as well as phosphorylation of AMP-activated kinase (AMPK). The AKT-mammalian target of the rapamycin (mTOR) signal pathway, which is important for muscle protein synthesis, was increased in LL-administered groups. The HPLC analysis and pharmacological test revealed that quercetin 3-O-beta-glucuronide (Q3G) is a major active component in LL. Thus, Q3G decreased the gene expression of atrogin-1 and MuRF1 and phosphorylation of AMPK. This compound also increased phosphorylation levels of mTOR and its upstream enzyme AKT in DEX-treated C2C12 cells. We identified that LL improves muscle wasting through regulation of muscle protein metabolism in DEX-induced muscle atrophy mice. Q3G is predicted to be one of the major active phenolic components in LL. Therefore, we propose LL as a supplement or therapeutic agent to prevent or treat muscle wasting, such as sarcopenia.

Phenotypic regulation of animal skeletal muscle protein metabolism

This review highlights the current state of phenotypic mechanisms of regulation of muscle protein metabolism in animals. Since the skeletal muscle represents 40–50% of body mass in mammals it is a critical regulator of overall metabolism. Therefore, an understanding of the processes involved in the postnatal increase in muscle mass, with associated accumulation of protein, is fundamental. Throughout life, a delicate balance exists between protein synthesis and degradation that is essential for growth and normal health of humans and animals. Signaling pathways coordinate muscle protein balance. Anabolic and catabolic stimuli are integrated through the PKB/Akt-mTORC1 signaling to regulate mechanisms that control muscle protein synthesis and breakdown. At an early periods of intensive growth, muscle mass is stimulated by an increase in protein synthesis at the level of mRNA translation. Throughout the life, proteolytic processes including autophagy lysosomal system, ubiquitin proteasome pathway, calcium-dependent calpains and cysteine protease caspase enzyme cascade influence the growth of muscle mass. Several signal transmission networks direct and coordinate these processes along with quality control mechanisms to maintain protein homeostasis (proteostasis). Genetic factors, hormones, amino acids, phytoecdysteroids, and rhodanines affect the protein metabolism via signaling pathways, changing the ability and / or efficiency of muscle growth.

Physical decline and survival in the elderly are affected by the genetic variability of amino acid transporter genes.

Amino acid (AA) availability is a rate-limiting factor in the regulation of muscle protein metabolism and, consequently, a risk factor for age-related decline in muscle performance. AA transporters are emerging as sensors of AA availability and activators of mTORC1 signalling, acting as transceptors. Here, we evaluated the association of 58 single nucleotide polymorphisms (SNPs) in 10 selected AA transporter genes with parameters of physical performance (Hand Grip, Activity of Daily Living, Walking time). By analysing a sample of 475 subjects aged 50-89 years, we found significant associations with SLC7A5/LAT1, SLC7A8/LAT2, SLC36A1/PAT1, SLC38A2/SNAT2, SLC3A2/CD98, SLC38A7/SNAT7 genes. Further investigation of the SNPs in a cross-sectional study including 290 subjects aged 90-107 years revealed associations of SLC3A2/CD98, SLC38A2/SNAT2, SLC38A3/SNAT3, SLC38A9/SNAT9 variability with longevity. Finally, a longitudinal study examining the survival rate over 10 years showed age-dependent complexity due to possible antagonistic pleiotropic effects for a SNP in SLC38A9/SNAT9, conferring a survival advantage before 90 years of age and a disadvantage later, probably due to the remodelling of AA metabolism. On the whole, our findings support the hypothesis that AA transporters may impact on the age-related physical decline and survival at old age in a complex way, likely through a mechanism involving mTORC1 signalling.

Regulation of muscle protein metabolism by nutrition and exercise

Regulation of muscle protein metabolism by nutrition and exercise

MECHANISMS IN ENDOCRINOLOGY: Exogenous insulin does not increase muscle protein synthesis rate when administered systemically: a systematic review

Though it is well appreciated that insulin plays an important role in the regulation of muscle protein metabolism, there is much discrepancy in the literature on the capacity of exogenous insulin administration to increase muscle protein synthesis rates in vivo in humans. To assess whether exogenous insulin administration increases muscle protein synthesis rates in young and older adults. A systematic review of clinical trials was performed and the presence or absence of an increase in muscle protein synthesis rate was reported for each individual study arm. In a stepwise manner, multiple models were constructed that excluded study arms based on the following conditions: model 1, concurrent hyperaminoacidemia; model 2, insulin-induced hypoaminoacidemia; model 3, supraphysiological insulin concentrations; and model 4, older, more insulin resistant, subjects. From the presented data in the current systematic review, we conclude that: i) exogenous insulin and amino acid administration effectively increase muscle protein synthesis, but this effect is attributed to the hyperaminoacidemia; ii) exogenous insulin administered systemically induces hypoaminoacidemia which obviates any insulin-stimulatory effect on muscle protein synthesis; iii) exogenous insulin resulting in supraphysiological insulin levels exceeding 50, 000 pmol/l may effectively augment muscle protein synthesis; iv) exogenous insulin may have a diminished effect on muscle protein synthesis in older adults due to age-related anabolic resistance; and v) exogenous insulin administered systemically does not increase muscle protein synthesis in healthy, young adults.

Fighting Sarcopenia in Older Frail Subjects: Protein Fuel for Strength, Exercise for Mass

Skeletal muscle has a global impact on our health not only because it permits us to stand or to move but also because of its numerous metabolic activities, including its capacities to produce energy from the mitochondrial oxidation of substrate or to deliver amino acids to the body in case of higher needs. Muscle mass loss together with alterations of muscle function, also defined as sarcopenia, is an important part of the frailty syndrome leading to disability, dependence, and increased mortality in the older subjects. Sarcopenia occurs not only with aging; chronic diseases are associated with loss of muscle mass and function too. Therefore, it is of major interest to understand how targeted therapeutic interventions, especially through food intake and physical exercise, are able to promote muscle mass and function in older persons through their specific impact on the regulation of muscle protein metabolism.

Cytokines

This review highlights the role of cytokines, in particular tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), in relation to the nature of human in-vivo muscle wasting in disease. Infusion of human TNF-α and IL-6 in healthy individuals, acutely raises TNF-α and IL-6 to moderate levels, has only identified IL-6 as a potent cytokine, decreasing systemic amino acid levels and muscle protein metabolism. The marked decrease in circulatory and muscle amino acid concentrations was observed with a concomitant reduction in both the rates of muscle protein synthesis and breakdown, that is, reduced turnover with a minor increase in net muscle degradation. Very similar observations have been made in models of acute inflammation, induced by high-dose endotoxin injection. However, these changes were suggested not to be attributed to a direct effect of IL-6 on the regulation of muscle protein metabolism but indirectly via IL-6 reducing amino acid availability. Recent studies suggest that the best described cytokines TNF-α and IL-6 are unlikely to be the major direct mediators of muscle protein loss in inflammatory diseases. However, these cytokines can initiate important changes in secondary mediators and/or clinical complications that need correction therapies causing muscle wasting. Moreover, the general view from animal work is that in muscle wasting the rate of muscle protein synthesis is decreased and the rate of breakdown is increased. However, this does not seem applicable for inflammatory diseases or human models of sepsis, in which the enhanced imbalance between these two processes is observed within an enhanced, normal or reduced muscle protein turnover.

Anti‐inflammation – just another word for anti‐ageing?

Sarcopenia, the Greek term for ‘poverty of flesh’, refers to age-associated loss of muscle mass and strength. The cost of ageing is a potential unmanageable burden for society and ageing-related diseases remain a major challenge to the national healthcare systems. However, in order to develop efficient strategies for treating age-related disorders, including sarcopenia, it is mandatory to unravel the mechanisms underlying the biology of ageing (Johnston et al. 2008). Sarcopenia is a multifactorial condition with contributing factors that may include loss of alpha-motoneuron input, changes in anabolic hormones, and decline in physical activity level. The typical sarcopenic phenotype includes a shift in fibre-type distribution, loss in force-generating capacity, loss of muscle mass and strength, and impaired performance of daily-life activities. However, sarcopenia may also be viewed as a condition driven by pro-inflammatory cytokines. Accordingly, a key question is whether sarcopenia is truly a distinct syndrome or a less aggressive form of a cachexia continuum. Muscle loss results from an imbalance between protein synthesis and degradation. This imbalance is not easily detectable when basal rates of protein turnover are measured, but is detected in the postprandial state in old rats and elderly humans, when fed a normal protein meal (Johnston et al. 2008). Although the signalling pathways and mechanisms whereby inflammation inhibits muscle protein synthesis are not fully understood, a recent mechanistic study published in The Journal of Physiology (Rieu et al. 2009) lends strong support to the hypothesis that chronic inflammation is an important player in sarcopenia and muscle weakness. They demonstrate that prevention of low-grade systemic inflammation by chronic administration of ibuprofen maintains the anabolic effect of food intake on the regulation of muscle protein metabolism in old rats. Both muscle proteolysis and protein synthesis were insensitive to food intake, whereas decrease of low-grade inflammation by ibuprofen restored protein synthesis. The anti-inflammatory rationale may be of importance not only with regard to maintenance of muscle mass, but with regard to several ageing-associated chronic diseases. Ageing is associated with chronic low-grade systemic inflammation, or ‘inflamm-ageing’ and accompanies several chronic non-communicable diseases (CNCDs). Evidence exists that inflammation is involved in mediating insulin resistance, atherosclerosis, neurodegeneration and tumour growth. In continuation, systemic low-grade inflammation appears to be a key player in the development of type 2 diabetes, cardiovascular diseases, Alzheimer's disease and cancer. Targeting inflammation may therefore provide a potential treatment not only for sarcopenia, but also for the prevention of a number of chronic age-associated diseases (Pedersen, 2009). While the study by Rieu et al. (2009) convincingly provides a link between inflammation and muscle protein metabolism in rats, there is still a gap to fill with regard to the clinical relevance of this finding. It remains to be shown if non-steroidal anti-inflammatory drugs can be safely administered to humans to obtain systemic concentrations that will in fact counteract inflammation-induced inhibition of protein synthesis. The therapeutic potential of high-dose anti-inflammatory drugs has been limited by bleeding risk. However, recent evidence has pointed at the potential of, for example, salsalate, a dimer of salicylic acid, which has an established safety profile and is an equipotent inhibitor of NF-κB while at the same time having a lower bleeding risk than, for example, aspirin. Salsalate has promising effects on inflammation-induced insulin resistance (Fleischman et al. 2008). Hopefully, other clinical studies will evaluate whether non-steroidal anti-inflammatory drugs may counteract inflammation-induced loss of muscle mass in humans. Meanwhile, it is suggested that elderly people should be encouraged to avoid a physically inactive life style. Substantial evidence exists that regular exercise decreases systemic low-grade inflammation. Given that regular exercise offers protection against loss of muscle mass, type 2 diabetes, cardiovascular diseases, Alzheimer's disease and some cancers, it is suggested that regular exercise may exert some of its beneficial health effects by inducing anti-inflammatory actions. Regular exercise, including strength training, represents a low-risk low-cost, but highly efficient mode to combat chronic inflammation in the elderly. In future, targeting inflammation, either with drugs or exercise, may prove to constitute an efficient anti-ageing cure.

TNFα‐308G/A Genotype is Associated with Muscle Mass in Humans

PURPOSE: Tumor necrosis factor alpha (TNFa) has been implicated in the regulation of muscle protein metabolism. A promoter polymorphism in the TNFa gene (TNFa −308 G/A) has been associated with higher production of TNFa. In this study, the relationship between TNFa −308G/A genotype and muscle mass was investigated in adult individuals. METHODS: 1095 participants of Baltimore Longitudinal Study of Aging (BLSA) (age range: 19 to 97 yr, 529 females and 566 males) were genotyped for TNFa −308G/A. Skeletal muscle mass (measured by DXA) was compared among different genotype groups. Age, gender, race and height were accounted for as confounding factors. RESULTS: TNFa genotype was significantly associated with both total body lean mass (LM) (p<0.0001) and appendicular skeletal muscle mass (ASMM) (p=0.0021). The AA genotype group (n=28) had higher muscle mass than the GA and GG groups (n=306 and 760) (LM: 68.1±2.2 vs. 56.2±0.6 and 56.6±0.4kg, p<0.0001; ASMM: 29.4 ±1.3 vs. 24.1±0.4 and 24.3±0.3kg, p=0.0006). Due to limitation in sample sizes, further analysis in subgroups only showed significant associations between TNFa genotype and muscle mass in white males (LM: P<0.0001; ASMM: p=0.0016). CONCLUSIONS: TNFa −308G/A genotype was significantly associated with muscle mass, with AA homozygotes having higher muscle mass than G allele carriers in healthy individuals. Supported by intramural NIH-NIA funds, AG21500 and AG22791.

Phosphatidylinositol 3-kinase and p70 s6 kinase participate in the regulation of protein turnover in skeletal muscle by insulin and insulin-like growth factor I.

This study was designed to evaluate the role of phosphatidylinositol (PI3) kinase, p70 S6 kinase (p70S6K), and mitogen-activated protein (MAP) kinase in the regulation of muscle protein metabolism by insulin and insulin-like growth factor I (IGF-I). Wortmannin and LY294002 (inhibitors of P13 kinase) both abolished the stimulation of protein synthesis by insulin or IGF-I in epitrochlearis muscle incubated in vitro. LY294002 also totally reversed the antiproteolytic action of these hormones. Although p70S6K activation by insulin and IGF-I may be mediated by PI3 kinase in epitrochlearis muscle, the specific inhibition of this kinase by rapamycin caused only partial (25%) inhibition of the stimulation of protein synthesis by these two hormones. Rapamycin had no effect on proteolysis. Finally, insulin or IGF-I did not stimulate MAP kinase activity at any of the times tested (2-25 min), suggesting that this protein kinase was not directly involved in the regulation of muscle protein metabolism. These observations provide evidence that PI3 kinase and p70S6K, but not MAP kinase, play a role in the regulation of muscle protein turnover by insulin or IGF-I.

Phosphatidylinositol 3-kinase and p70 s6 kinase participate in the regulation of protein turnover in skeletal muscle by insulin and insulin-like growth factor I

This study was designed to evaluate the role of phosphatidylinositol (PI3) kinase, p70 S6 kinase (p70S6K), and mitogen-activated protein (MAP) kinase in the regulation of muscle protein metabolism by insulin and insulin-like growth factor I (IGF-I). Wortmannin and LY294002 (inhibitors of P13 kinase) both abolished the stimulation of protein synthesis by insulin or IGF-I in epitrochlearis muscle incubated in vitro. LY294002 also totally reversed the antiproteolytic action of these hormones. Although p70S6K activation by insulin and IGF-I may be mediated by PI3 kinase in epitrochlearis muscle, the specific inhibition of this kinase by rapamycin caused only partial (25%) inhibition of the stimulation of protein synthesis by these two hormones. Rapamycin had no effect on proteolysis. Finally, insulin or IGF-I did not stimulate MAP kinase activity at any of the times tested (2-25 min), suggesting that this protein kinase was not directly involved in the regulation of muscle protein metabolism. These observations provide evidence that PI3 kinase and p70S6K, but not MAP kinase, play a role in the regulation of muscle protein turnover by insulin or IGF-I.

Regulation of muscle protein metabolism in sheep and lambs: nutritional, endocrine and genetic aspects

Muscle protein accretion, as with the body in general, increases with feed intake. Protein balance across hind limb muscles occurs at energy intakes less than energy balance in the animal as a whole. There is considerable between-sheep variation in muscle protein accretion, and in the relative rates of protein synthesis and degradation, which are in part due to inherent differences in growth potential. Lambs selected for high weight at weaning deposit proportionately more nitrogen in the body than those selected for low weight at weaning. Inherently faster growing lambs have lower rates of protein breakdown in muscle and whole body than those which exhibit slower growth. Differences in sensitivity to insulin and plasma concentration of insulin-like growth factor-1 (IGF-1) indicate that the inherent differences in growth are associated with differences in responsiveness of muscle to hormones, and possible direct effects of IGF-1. Arteriovenous difference methodology, and isotope dilution, have been important tools in improving our understanding of the regulation of muscle protein metabolism.