Interventional strategies to combat muscle disuse atrophy in humans: focus on neuromuscular electrical stimulation and dietary protein

Numerous situations, such as the recovery from illness or rehabilitation after injury, necessitate a period of muscle disuse in otherwise healthy individuals. Even a few days of immobilization or bed rest can lead to substantial loss of skeletal muscle tissue and compromise metabolic health. The decline in muscle mass is attributed largely to a decline in postabsorptive and postprandial muscle protein synthesis rates. Reintroduction of some level of muscle contraction by the application of neuromuscular electrical stimulation (NMES) can augment both postabsorptive and postprandial muscle protein synthesis rates and, as such, prevent or attenuate muscle loss during short-term disuse in various clinical populations. Whereas maintenance of habitual dietary protein consumption is a prerequisite for muscle mass maintenance, supplementing dietary protein above habitual intake levels does not prevent muscle loss during disuse in otherwise healthy humans. Combining the anabolic properties of physical activity (or surrogates) with appropriate nutritional support likely further increases the capacity to preserve skeletal muscle mass during a period of disuse. Therefore, effective interventional strategies to prevent or alleviate muscle disuse atrophy should include both exercise (mimetics) and appropriate nutritional support.

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Human Skeletal Muscle Disuse Atrophy: Effects on Muscle Protein Synthesis, Breakdown, and Insulin Resistance—A Qualitative Review

Frontiers in Physiology ◽

10.3389/fphys.2016.00361 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 52

Author(s):

Supreeth S. Rudrappa ◽

Daniel J. Wilkinson ◽

Paul L. Greenhaff ◽

Kenneth Smith ◽

Iskandar Idris ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Synthesis ◽

Human Skeletal Muscle ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Disuse Atrophy ◽

Qualitative Review ◽

Muscle Disuse

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Characterising the muscle anabolic potential of dairy, meat and plant-based protein sources in older adults

Proceedings of The Nutrition Society ◽

10.1017/s002966511700194x ◽

2017 ◽

Vol 77 (1) ◽

pp. 20-31 ◽

Cited By ~ 48

Author(s):

Stefan H. M. Gorissen ◽

Oliver C. Witard

Keyword(s):

Older Adults ◽

Skeletal Muscle ◽

Amino Acid ◽

Muscle Mass ◽

Dietary Protein ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Amino Acid Profile ◽

Protein Sources ◽

Age Related

The age-related loss of skeletal muscle mass and function is caused, at least in part, by a reduced muscle protein synthetic response to protein ingestion. The magnitude and duration of the postprandial muscle protein synthetic response to ingested protein is dependent on the quantity and quality of the protein consumed. This review characterises the anabolic properties of animal-derived and plant-based dietary protein sources in older adults. While approximately 60 % of dietary protein consumed worldwide is derived from plant sources, plant-based proteins generally exhibit lower digestibility, lower leucine content and deficiencies in certain essential amino acids such as lysine and methionine, which compromise the availability of a complete amino acid profile required for muscle protein synthesis. Based on currently available scientific evidence, animal-derived proteins may be considered more anabolic than plant-based protein sources. However, the production and consumption of animal-derived protein sources is associated with higher greenhouse gas emissions, while plant-based protein sources may be considered more environmentally sustainable. Theoretically, the lower anabolic capacity of plant-based proteins can be compensated for by ingesting a greater dose of protein or by combining various plant-based proteins to provide a more favourable amino acid profile. In addition, leucine co-ingestion can further augment the postprandial muscle protein synthetic response. Finally, prior exercise or n-3 fatty acid supplementation have been shown to sensitise skeletal muscle to the anabolic properties of dietary protein. Applying one or more of these strategies may support the maintenance of muscle mass with ageing when diets rich in plant-based protein are consumed.

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Targeting the Gut Microbiota to Improve Dietary Protein Efficacy to Mitigate Sarcopenia

Frontiers in Nutrition ◽

10.3389/fnut.2021.656730 ◽

2021 ◽

Vol 8 ◽

Author(s):

Elena de Marco Castro ◽

Caoileann H. Murphy ◽

Helen M. Roche

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Gut Microbiota ◽

Muscle Mass ◽

Dietary Protein ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Low Grade ◽

Ageing Population ◽

Anabolic Resistance

Sarcopenia is characterised by the presence of diminished skeletal muscle mass and strength. It is relatively common in older adults as ageing is associated with anabolic resistance (a blunted muscle protein synthesis response to dietary protein consumption and resistance exercise). Therefore, interventions to counteract anabolic resistance may benefit sarcopenia prevention and are of utmost importance in the present ageing population. There is growing speculation that the gut microbiota may contribute to sarcopenia, as ageing is also associated with [1) dysbiosis, whereby the gut microbiota becomes less diverse, lacking in healthy butyrate-producing microorganisms and higher in pathogenic bacteria, and [2) loss of epithelial tight junction integrity in the lining of the gut, leading to increased gut permeability and higher metabolic endotoxemia. Animal data suggest that both elements may impact muscle physiology, but human data corroborating the causality of the association between gut microbiota and muscle mass and strength are lacking. Mechanisms wherein the gut microbiota may alter anabolic resistance include an attenuation of gut-derived low-grade inflammation and/or the increased digestibility of protein-containing foods and consequent higher aminoacidemia, both in favour of muscle protein synthesis. This review focuses on the putative links between the gut microbiota and skeletal muscle in the context of sarcopenia. We also address the issue of plant protein digestibility because plant proteins are increasingly important from an environmental sustainability perspective, yet they are less efficient at stimulating muscle protein synthesis than animal proteins.

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Physiologic and molecular bases of muscle hypertrophy and atrophy: impact of resistance exercise on human skeletal muscle (protein and exercise dose effects)This paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

Applied Physiology Nutrition and Metabolism ◽

10.1139/h09-042 ◽

2009 ◽

Vol 34 (3) ◽

pp. 403-410 ◽

Cited By ~ 67

Author(s):

Stuart M. Phillips

Keyword(s):

Skeletal Muscle ◽

Resistance Exercise ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Protein ◽

Peer Review Process ◽

Muscle Protein Synthesis ◽

Common Finding ◽

Disuse Atrophy ◽

Age Related

Normally, skeletal muscle mass is unchanged, beyond periods of growth, but it begins to decline in the fourth or fifth decade of life. The mass of skeletal muscle is maintained by ingestion of protein-containing meals. With feeding, muscle protein synthesis (MPS) is stimulated and a small suppression of muscle protein breakdown (MPB) occurs, such that protein balance becomes positive (MPS > MPB). As the postprandial period subsides and a transition toward fasting occurs, the balance of muscle protein turnover becomes negative again (MPB > MPS). Thus, during maintenance of skeletal muscle mass, the long-term net result is that MPS is balanced by MPB. Acutely, however, it is of interest to determine what regulates feeding-induced increases in MPS, since it appears that, in a number of scenarios (for example aging, disuse, and wasting diseases), a suppression of MPS in response to feeding is a common finding. In fact, recent findings point to the fact that loss of skeletal muscle mass with disuse and aging is due not chronic changes in MPS or MPB, but to a blunted feeding-induced rise in MPS. Resistance exercise is a potent stimulator of MPS and appears to synergistically enhance the gains stimulated by feeding. As such, resistance exercise is an important countermeasure to disuse atrophy and to age-related declines in skeletal muscle mass. What is less well understood is how the intensity and volume of the resistance exercise stimulus is sufficient to result in rises in MPS. Recent advances in this area are discussed here, with a focus on human in vivo data.

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Dietary Protein and Muscle in Aging People: The Potential Role of the Gut Microbiome

10.20944/preprints201806.0152.v1 ◽

2018 ◽

Author(s):

Mary Ni Lochlainn ◽

Ruth C. E. Bowyer ◽

Claire J. Steves

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Dietary Protein ◽

Gut Microbiome ◽

Muscle Function ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Skeletal Muscle Function ◽

Anabolic Resistance

Muscle mass, strength and physical function are known to decline with age. This is associated with the development of geriatric syndromes including sarcopenia and frailty. These conditions are associated with disability, falls, longer hospital stay, higher readmission rates, institutionalisation, osteoporosis, and death. Moreover, they are associated with reduced quality of life, as well as substantial costs to health services around the world. Dietary protein is essential for skeletal muscle function. Older adults have shown evidence of anabolic resistance, where greater amounts of protein are required to stimulate muscle protein synthesis and therefore require higher daily amounts of dietary protein. Research shows that resistance exercise has the most beneficial effect on preserving skeletal muscle. A synergistic effect has been noted when this is combined with dietary protein, yet studies in this area lack consistency. This is due, in part, to the variation that exists within dietary protein, in terms of dose, quality, source, amino acid composition and timing. Research has targeted participants that are replete in dietary protein with negative results. Inconsistent measures of muscle mass, muscle function, physical activity and diet are used. This review attempts to summarise these issues, as well as introduce the possible role of the gut microbiome and its metabolome in this area.

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Diminished anabolic signaling response to insulin induced by intramuscular lipid accumulation is associated with inflammation in aging but not obesity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00198.2015 ◽

2016 ◽

Vol 310 (7) ◽

pp. R561-R569 ◽

Cited By ~ 40

Author(s):

Donato A. Rivas ◽

Devin J. McDonald ◽

Nicholas P. Rice ◽

Prashanth H. Haran ◽

Gregory G. Dolnikowski ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Lipid Accumulation ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Insulin Response ◽

Muscle Loss ◽

Bioactive Lipids

The loss of skeletal muscle mass is observed in many pathophysiological conditions, including aging and obesity. The loss of muscle mass and function with aging is defined as sarcopenia and is characterized by a mismatch between skeletal muscle protein synthesis and breakdown. Characteristic metabolic features of both aging and obesity are increases in intramyocellular lipid (IMCL) content in muscle. IMCL accumulation may play a mechanistic role in the development of anabolic resistance and the progression of muscle atrophy in aging and obesity. In the present study, aged and high-fat fed mice were used to determine mechanisms leading to muscle loss. We hypothesized the accumulation of bioactive lipids in skeletal muscle, such as ceramide or diacylglycerols, leads to insulin resistance with aging and obesity and the inability to activate protein synthesis, contributing to skeletal muscle loss. We report a positive association between bioactive lipid accumulation and the loss of lean mass and muscle strength. Obese and aged animals had significantly higher storage of ceramide and diacylglycerol compared with young. Furthermore, there was an attenuated insulin response in components of the mTOR anabolic signaling pathway. We also observed differential increases in the expression of inflammatory cytokines and the phosphorylation of IκBα with aging and obesity. These data challenge the accepted role of increased inflammation in obesity-induced insulin resistance in skeletal muscle. Furthermore, we have now established IκBα with a novel function in aging-associated muscle loss that may be independent of its previously understood role as an NF-κB inhibitor.

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Knockdown of the E3 ubiquitin ligase UBR5 and its role in skeletal muscle anabolism

AJP Cell Physiology ◽

10.1152/ajpcell.00432.2020 ◽

2021 ◽

Vol 320 (1) ◽

pp. C45-C56

Author(s):

David C. Hughes ◽

Daniel C. Turner ◽

Leslie M. Baehr ◽

Robert A. Seaborne ◽

Mark Viggars ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Ubiquitin Ligase ◽

Fluorescent Protein ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Tibialis Anterior Muscle ◽

E3 Ubiquitin Ligase ◽

Skeletal Muscle Atrophy ◽

The Impact

UBR5 is an E3 ubiquitin ligase positively associated with anabolism, hypertrophy, and recovery from atrophy in skeletal muscle. The precise mechanisms underpinning UBR5’s role in the regulation of skeletal muscle mass remain unknown. The present study aimed to elucidate these mechanisms by silencing the UBR5 gene in vivo. To achieve this aim, we electroporated a UBR5-RNAi plasmid into mouse tibialis anterior muscle to investigate the impact of reduced UBR5 on anabolic signaling MEK/ERK/p90RSK and Akt/GSK3β/p70S6K/4E-BP1/rpS6 pathways. Seven days after UBR5 RNAi electroporation, although reductions in overall muscle mass were not detected, the mean cross-sectional area (CSA) of green fluorescent protein (GFP)-positive fibers were reduced (−9.5%) and the number of large fibers were lower versus the control. Importantly, UBR5-RNAi significantly reduced total RNA, muscle protein synthesis, ERK1/2, Akt, and GSK3β activity. Although p90RSK phosphorylation significantly increased, total p90RSK protein levels demonstrated a 45% reduction with UBR5-RNAi. Finally, these early events after 7 days of UBR5 knockdown culminated in significant reductions in muscle mass (−4.6%) and larger reductions in fiber CSA (−18.5%) after 30 days. This was associated with increased levels of phosphatase PP2Ac and inappropriate chronic elevation of p70S6K and rpS6 between 7 and 30 days, as well as corresponding reductions in eIF4e. This study demonstrates that UBR5 plays an important role in anabolism/hypertrophy, whereby knockdown of UBR5 culminates in skeletal muscle atrophy.

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Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.1.r133 ◽

2001 ◽

Vol 281 (1) ◽

pp. R133-R139 ◽

Cited By ~ 20

Author(s):

S. E. Samuels ◽

A. L. Knowles ◽

T. Tilignac ◽

E. Debiton ◽

J. C. Madelmont ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Cancer Cachexia ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Human Condition ◽

Skeletal Muscle Protein ◽

Tumor Bearing

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12CIN3O4S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower ( P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (−38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (∼−54 to −69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (−80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

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Testosterone suppression does not exacerbate disuse atrophy and impairs muscle recovery that is not rescued by high protein

Journal of Applied Physiology ◽

10.1152/japplphysiol.00752.2019 ◽

2020 ◽

Vol 129 (1) ◽

pp. 5-16 ◽

Cited By ~ 2

Author(s):

Erik D. Hanson ◽

Andrew C. Betik ◽

Cara A. Timpani ◽

John Tarle ◽

Xinmei Zhang ◽

...

Keyword(s):

Skeletal Muscle ◽

Adverse Effects ◽

Muscle Mass ◽

Caloric Intake ◽

Disuse Atrophy ◽

Muscle Recovery ◽

Testosterone Levels ◽

Muscle Disuse ◽

Low Testosterone ◽

And Function

Low testosterone levels during skeletal muscle disuse did not worsen declines in muscle mass and function, although hypogonadism may attenuate recovery during subsequent reloading. Diets high in casein did not improve outcomes during immobilization or reloading. Practical strategies are needed that do not compromise caloric intake yet provide effective protein doses to augment these adverse effects.

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