Abstract
A variety of internal and external factors such as exercise, nutrition, inflammation, and cancer‐associated cachexia affect the regulation of skeletal muscle mass. Because skeletal muscle functions as a crucial regulator of whole body metabolism, rather than just as a motor for locomotion, the enhancement and maintenance of muscle mass and function are required to maintain health and reduce the morbidity and mortality associated with diseases involving muscle wasting. Recent studies in this field have made tremendous progress; therefore, identification of the mechanisms that regulate skeletal muscle mass is necessary for the physical and nutritional management of both athletes and patients with muscle wasting disease. In this review, we present an overall picture of the interactions regulating skeletal muscle mass, particularly focusing on the insulin‐like growth factor‐I (IGF‐I)/insulin‐Akt‐mammalian target of rapamycin (mTOR) pathway, skeletal muscle inactivity, and endurance and resistance exercise. We also discuss the contribution of nitric oxide (NO) to the regulation of skeletal muscle mass based on the current knowledge of the novel role of NO in these processes.
Highlights
Increasing muscle strength and maintaining muscle mass and function are necessary for athletes and for aging people; rather than just as a motor for locomotion, skeletal muscle functions as a crucial regulator of whole body metabolism.[1,2] Systemic wasting conditions cause the rapid loss of muscle mass, weakness, and increased disability, reducing the quality of life, and are directly linked to mortality.[3]
No changes were observed in PGC‐1α1 levels with β‐adrenergic agonist treatment. These results show that PGC‐1α4 is required for myotubule hypertrophy in their cellular model.[56]
Low physical activity, malnutrition, inflammation, and cancer‐associated cachexia all account for skeletal muscle wasting, which substantially reduces the quality of life
Summary
Increasing muscle strength and maintaining muscle mass and function are necessary for athletes and for aging people; rather than just as a motor for locomotion, skeletal muscle functions as a crucial regulator of whole body metabolism.[1,2] Systemic wasting conditions cause the rapid loss of muscle mass, weakness, and increased disability, reducing the quality of life, and are directly linked to mortality.[3]. AMP/ATP, adenosine monophosphate/adenosine triphosphate; AMPK, AMP‐activated protein kinase; ATGs, autophagy‐ related genes; DGC, dystrophin glycoprotein complex; FoxO, Fork head box O; GRP94, glucose‐regulated protein 94; IGR‐I, insulin‐like growth factor‐I; IR/IRS, insulin receptor/ insulin receptor substrate; MAFbx, muscle atrophy F box; mTOR, mammalian target of rapamycin; MuRF‐1, muscle ring finger 1; nNOSμ, neuronal nitric oxide synthase μ; NO, nitric oxide; ROS, reactive oxygen species; RyR1, type 1 ryanodine receptor; SR, sarcoplasmic reticulum; TFEB, transfactor EB; UPS, ubiquitin proteasome system activity of lipoprotein lipases and the subcellular distribution of CD36 for fatty acid uptake by skeletal muscle cells.[23] This is caused by decreased IGF‐I/insulin‐Akt‐mTOR signaling and the subsequent translocation of dephosphorylated FoxO and TFEB to the nucleus, followed by the enhanced transcription of atrogenes and muscle protein degradation through the UPS Another important factor affecting the IGF‐1/insulin‐Akt‐ mTOR pathway in the regulation of skeletal muscle mass is myostatin, an extracellular cytokine (a member of transforming growth factor‐β (TGF‐β) superfamily) mostly expressed by skeletal muscle, and a potent negative regulator of muscle growth and the activation of satellite cells (stem cells resident in skeletal muscle).[24] During embryogenesis, myostatin expression is restricted to the developing skeletal muscles. These findings have been confirmed in many human studies using beetroot juice as the source of nitrate,[74,75] which may provide a promising nutritional strategy for promoting skeletal muscle performance
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