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1.
Molecular Mechanisms of Muscle Fatigue.
Constantin-Teodosiu, D, Constantin, D
International journal of molecular sciences. 2021;(21)
Abstract
Muscle fatigue (MF) declines the capacity of muscles to complete a task over time at a constant load. MF is usually short-lasting, reversible, and is experienced as a feeling of tiredness or lack of energy. The leading causes of short-lasting fatigue are related to overtraining, undertraining/deconditioning, or physical injury. Conversely, MF can be persistent and more serious when associated with pathological states or following chronic exposure to certain medication or toxic composites. In conjunction with chronic fatigue, the muscle feels floppy, and the force generated by muscles is always low, causing the individual to feel frail constantly. The leading cause underpinning the development of chronic fatigue is related to muscle wasting mediated by aging, immobilization, insulin resistance (through high-fat dietary intake or pharmacologically mediated Peroxisome Proliferator-Activated Receptor (PPAR) agonism), diseases associated with systemic inflammation (arthritis, sepsis, infections, trauma, cardiovascular and respiratory disorders (heart failure, chronic obstructive pulmonary disease (COPD))), chronic kidney failure, muscle dystrophies, muscle myopathies, multiple sclerosis, and, more recently, coronavirus disease 2019 (COVID-19). The primary outcome of displaying chronic muscle fatigue is a poor quality of life. This type of fatigue represents a significant daily challenge for those affected and for the national health authorities through the financial burden attached to patient support. Although the origin of chronic fatigue is multifactorial, the MF in illness conditions is intrinsically linked to the occurrence of muscle loss. The sequence of events leading to chronic fatigue can be schematically denoted as: trigger (genetic or pathological) -> molecular outcome within the muscle cell -> muscle wasting -> loss of muscle function -> occurrence of chronic muscle fatigue. The present review will only highlight and discuss current knowledge on the molecular mechanisms that contribute to the upregulation of muscle wasting, thereby helping us understand how we could prevent or treat this debilitating condition.
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2.
Molecular and cellular basis of genetically inherited skeletal muscle disorders.
Dowling, JJ, Weihl, CC, Spencer, MJ
Nature reviews. Molecular cell biology. 2021;(11):713-732
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Abstract
Neuromuscular disorders comprise a diverse group of human inborn diseases that arise from defects in the structure and/or function of the muscle tissue - encompassing the muscle cells (myofibres) themselves and their extracellular matrix - or muscle fibre innervation. Since the identification in 1987 of the first genetic lesion associated with a neuromuscular disorder - mutations in dystrophin as an underlying cause of Duchenne muscular dystrophy - the field has made tremendous progress in understanding the genetic basis of these diseases, with pathogenic variants in more than 500 genes now identified as underlying causes of neuromuscular disorders. The subset of neuromuscular disorders that affect skeletal muscle are referred to as myopathies or muscular dystrophies, and are due to variants in genes encoding muscle proteins. Many of these proteins provide structural stability to the myofibres or function in regulating sarcolemmal integrity, whereas others are involved in protein turnover, intracellular trafficking, calcium handling and electrical excitability - processes that ensure myofibre resistance to stress and their primary activity in muscle contraction. In this Review, we discuss how defects in muscle proteins give rise to muscle dysfunction, and ultimately to disease, with a focus on pathologies that are most common, best understood and that provide the most insight into muscle biology.
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Direct or indirect regulation of muscle protein synthesis by energy status?
Moinard, C, Fontaine, E
Clinical nutrition (Edinburgh, Scotland). 2021;(4):1893-1896
Abstract
Muscle protein synthesis (MPS) is a complex and finely-regulated mechanism that plays a key role in muscle homeostasis. Amino acid bioavailability is widely considered a major driver of MPS regulation via mTOR pathway activation. However, recent results suggest that amino acid bioavailability affects cellular energy status. Whatever the tool used to modulate energy status (amino acid depletion or mild mitochondrial uncoupling), a decrease in cellular energy status decreases MPS, without necessarily involving the mTOR pathway. Here we propose that energy status directly regulates one or several energy-consuming step(s) during MPS. This new paradigm modifies our vision of protein metabolism and raises prospects for new advances in therapeutics.
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Evidence for the Contribution of Gut Microbiota to Age-Related Anabolic Resistance.
Watson, MD, Cross, BL, Grosicki, GJ
Nutrients. 2021;(2)
Abstract
Globally, people 65 years of age and older are the fastest growing segment of the population. Physiological manifestations of the aging process include undesirable changes in body composition, declines in cardiorespiratory fitness, and reductions in skeletal muscle size and function (i.e., sarcopenia) that are independently associated with mortality. Decrements in muscle protein synthetic responses to anabolic stimuli (i.e., anabolic resistance), such as protein feeding or physical activity, are highly characteristic of the aging skeletal muscle phenotype and play a fundamental role in the development of sarcopenia. A more definitive understanding of the mechanisms underlying this age-associated reduction in anabolic responsiveness will help to guide promyogenic and function promoting therapies. Recent studies have provided evidence in support of a bidirectional gut-muscle axis with implications for aging muscle health. This review will examine how age-related changes in gut microbiota composition may impact anabolic response to protein feeding through adverse changes in protein digestion and amino acid absorption, circulating amino acid availability, anabolic hormone production and responsiveness, and intramuscular anabolic signaling. We conclude by reviewing literature describing lifestyle habits suspected to contribute to age-related changes in the microbiome with the goal of identifying evidence-informed strategies to preserve microbial homeostasis, anabolic sensitivity, and skeletal muscle with advancing age.
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Muscle Protein Synthesis and Whole-Body Protein Turnover Responses to Ingesting Essential Amino Acids, Intact Protein, and Protein-Containing Mixed Meals with Considerations for Energy Deficit.
Gwin, JA, Church, DD, Wolfe, RR, Ferrando, AA, Pasiakos, SM
Nutrients. 2020;(8)
Abstract
Protein intake recommendations to optimally stimulate muscle protein synthesis (MPS) are derived from dose-response studies examining the stimulatory effects of isolated intact proteins (e.g., whey, egg) on MPS in healthy individuals during energy balance. Those recommendations may not be adequate during periods of physiological stress, specifically the catabolic stress induced by energy deficit. Providing supplemental intact protein (20-25 g whey protein, 0.25-0.3 g protein/kg per meal) during strenuous military operations that elicit severe energy deficit does not stimulate MPS-associated anabolic signaling or attenuate lean mass loss. This occurs likely because a greater proportion of the dietary amino acids consumed are targeted for energy-yielding pathways, whole-body protein synthesis, and other whole-body essential amino acid (EAA)-requiring processes than the proportion targeted for MPS. Protein feeding formats that provide sufficient energy to offset whole-body energy and protein-requiring demands during energy deficit and leverage EAA content, digestion, and absorption kinetics may optimize MPS under these conditions. Understanding the effects of protein feeding format-driven alterations in EAA availability and subsequent changes in MPS and whole-body protein turnover is required to design feeding strategies that mitigate the catabolic effects of energy deficit. In this manuscript, we review the effects, advantages, disadvantages, and knowledge gaps pertaining to supplemental free-form EAA, intact protein, and protein-containing mixed meal ingestion on MPS. We discuss the fundamental role of whole-body protein balance and highlight the importance of comprehensively assessing whole-body and muscle protein kinetics when evaluating the anabolic potential of varying protein feeding formats during energy deficit.
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Intramuscular Mechanisms Mediating Adaptation to Low-Carbohydrate, High-Fat Diets during Exercise Training.
Howard, EE, Margolis, LM
Nutrients. 2020;(9)
Abstract
Interest in low-carbohydrate, high-fat (LCHF) diets has increased over recent decades given the theorized benefit of associated intramuscular adaptations and shifts in fuel utilization on endurance exercise performance. Consuming a LCHF diet during exercise training increases the availability of fat (i.e., intramuscular triglyceride stores; plasma free fatty acids) and decreases muscle glycogen stores. These changes in substrate availability increase reliance on fat oxidation for energy production while simultaneously decreasing reliance on carbohydrate oxidation for fuel during submaximal exercise. LCHF diet-mediated changes in substrate oxidation remain even after endogenous or exogenous carbohydrate availability is increased, suggesting that the adaptive response driving changes in fat and carbohydrate oxidation lies within the muscle and persists even when the macronutrient content of the diet is altered. This narrative review explores the intramuscular adaptations underlying increases in fat oxidation and decreases in carbohydrate oxidation with LCHF feeding. The possible effects of LCHF diets on protein metabolism and post-exercise muscle remodeling are also considered.
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Muscle protein turnover and low-protein diets in patients with chronic kidney disease.
Garibotto, G, Picciotto, D, Saio, M, Esposito, P, Verzola, D
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(5):741-751
Abstract
Adaptation to a low-protein diet (LPD) involves a reduction in the rate of amino acid (AA) flux and oxidation, leading to more efficient use of dietary AA and reduced ureagenesis. Of note, the concept of 'adaptation' to low-protein intakes has been separated from the concept of 'accommodation', the latter term implying a decrease in protein synthesis, with development of wasting, when dietary protein intake becomes inadequate, i.e. beyond the limits of the adaptive mechanisms. Acidosis, insulin resistance and inflammation are recognized mechanisms that can increase protein degradation and can impair the ability to activate an adaptive response when an LPD is prescribed in a chronic kidney disease (CKD) patient. Current evidence shows that, in the short term, clinically stable patients with CKD Stages 3-5 can efficiently adapt their muscle protein turnover to an LPD containing 0.55-0.6 g protein/kg or a supplemented very-low-protein diet (VLPD) by decreasing muscle protein degradation and increasing the efficiency of muscle protein turnover. Recent long-term randomized clinical trials on supplemented VLPDs in patients with CKD have shown a very good safety profile, suggesting that observations shown by short-term studies on muscle protein turnover can be extrapolated to the long-term period.
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Protein Distribution and Muscle-Related Outcomes: Does the Evidence Support the Concept?
Hudson, JL, Iii, REB, Campbell, WW
Nutrients. 2020;(5)
Abstract
There is a shift in thinking about dietary protein requirements from daily requirements to individual meal requirements. Per meal, stimulation of muscle protein synthesis has a saturable dose relationship with the quantity of dietary protein consumed. Protein intake above the saturable dose does not further contribute to the synthetic response; the "excess" amino acids are predominantly oxidized. Given that daily dietary protein intake is finite, finding protein distribution patterns that both reduce amino acid oxidation and maximize their contribution towards protein synthesis (in theory improving net balance) could be "optimal" and is of practical scientific interest to promote beneficial changes in skeletal muscle-related outcomes. This article reviews both observational and randomized controlled trial research on the protein distribution concept. The current evidence on the efficacy of consuming an "optimal" protein distribution to favorably influence skeletal muscle-related changes is limited and inconsistent. The effect of protein distribution cannot be sufficiently disentangled from the effect of protein quantity. Consuming a more balanced protein distribution may be a practical way for adults with marginal or inadequate protein intakes (<0.80 g·kg-1·d-1) to achieve a moderately higher total protein intake. However, for adults already consuming 0.8-1.3 g·kg-1·d-1, the preponderance of evidence supports that consuming at least one meal that contains sufficient protein quantity to maximally stimulate muscle protein synthesis, independent of daily distribution, is helpful to promote skeletal muscle health.
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Myoferlin, a multifunctional protein in normal cells, has novel and key roles in various cancers.
Zhu, W, Zhou, B, Zhao, C, Ba, Z, Xu, H, Yan, X, Liu, W, Zhu, B, Wang, L, Ren, C
Journal of cellular and molecular medicine. 2019;(11):7180-7189
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Abstract
Myoferlin, a protein of the ferlin family, has seven C2 domains and exhibits activity in some cells, including myoblasts and endothelial cells. Recently, myoferlin was identified as a promising target and biomarker in non-small-cell lung cancer, breast cancer, pancreatic adenocarcinoma, hepatocellular carcinoma, colon cancer, melanoma, oropharyngeal squamous cell carcinoma, head and neck squamous cell carcinoma, clear cell renal cell carcinoma and endometrioid carcinoma. This evidence indicated that myoferlin was involved in the proliferation, invasion and migration of tumour cells, the mechanism of which mainly included promoting angiogenesis, vasculogenic mimicry, energy metabolism reprogramming, epithelial-mesenchymal transition and modulating exosomes. The roles of myoferlin in both normal cells and cancer cells are of great significance to provide novel and efficient methods of tumour treatment. In this review, we summarize recent studies and findings of myoferlin and suggest that myoferlin is a novel potential candidate for clinical diagnosis and targeted cancer therapy.
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The Muscle Protein Synthetic Response to Meal Ingestion Following Resistance-Type Exercise.
Trommelen, J, Betz, MW, van Loon, LJC
Sports medicine (Auckland, N.Z.). 2019;(2):185-197
Abstract
Protein ingestion following resistance-type exercise stimulates muscle protein synthesis rates and consequently enhances the skeletal muscle adaptive response to prolonged training. Ingestion of ~ 20 g of quickly digestible protein isolate optimizes muscle protein synthesis rates during the first few hours of post-exercise recovery. However, the majority of daily protein intake is consumed as slower digestible, nutrient-rich, whole-food protein sources as part of mixed meals. Therefore, the muscle protein synthetic response to the ingestion of protein supplements and typical foods or mixed meals may differ substantially. In addition, the muscle protein synthetic response to feeding is not only determined by acute nutrient intake but is also likely modulated by habitual energy and nutrient intake and nondietary factors such as habitual physical activity, body composition, age, and/or sex. Therefore, nutritional recommendations to maximize the muscle protein synthetic response to exercise depend on the type of meal (e.g., protein supplements vs. mixed meals) and the time until the next feeding opportunity (e.g., feeding before overnight sleep) and, therefore, need to be personalized to the individual athlete.