Introduction
Skeletal muscles support physical activity and generate large energy with muscle contraction. In addition, these muscles release various metabolic factors such as lactate, amino acids, and ammonia into circulation in response to physiological changes. Growing evidence has shown that muscle cells secrete also bioactive proteins, which have regulatory role in the muscles and other organs via endocrine, autocrine, or paracrine actions; this is the so-called myokine theory [
Adequate regular exercise has numerous health benefits. In the last few decades, epidemiological studies have shown that dietary–exercise regimen reduces the risk of various common diseases such as type 2 diabetes, cardiovascular disease, and carcinogenesis. In addition, regular exercise improves the prognosis of existing diseases, including diabetes, ischemic heart disease, heart failure, and chronic obstructive pulmonary disease. Accumulating evidence has demonstrated the mechanisms underlying the benefits of acute and regular exercise. A single bout of exercise drastically changes various physiological parameters such as hormone production, blood flow, and the activity of the nervous and immune system, in addition to altering the expression/activity of certain genes and proteins in the skeletal muscle. Further, regular exercise adaptively improves normal bodily functions including energy metabolism, muscle strength, brain-nervous system, endocrine system, and immune function, even in resting state, and the expression/activity of several key proteins in the skeletal muscle is involved in the development of this adaptation. The bioactive proteins secreted from the muscle would contribute in promoting health benefits along with maintaining physiological homeostasis and sports performance during exercise.
Metabolic and immune functions of muscle-secreted proteins
Previously, several proteins that are secreted from muscle cells into the extracellular environment in response to exercise have been reported. Many of them were suggested to be involved in the regulation of metabolic function in skeletal muscle itself and also in other metabolic organs. Interleukin (IL) -6 is a well-known secretory protein that is transiently elevated in muscles following a single bout of exercise [
In addition to IL-6, other muscle-secreted proteins such as brain-derived neurotrophic factor, fibroblast growth factor 21, IL-15, and myonectin have been shown to be produced in skeletal muscle in response to acute or chronic exercise, and have been suggested to increase fat oxidation or glucose uptake in skeletal muscles [
Anti-inflammation is another function suggested for muscle-secreted proteins, and muscle-derived IL-6 likely contributes to reduce inflammation when in circulation [
Myogenic function of muscle-secreted protein
Several proteins contribute to muscle hypertrophy via autocrine or paracrine effects. Insulin growth factor-1 (IGF-1) is known as a major hypertrophic inducer. It has been considered for long time that IGF-1 is generated by stimulating growth hormone in liver and secreted into circulation [
Myostatin, a member of the transforming growth factor-β family, is a negative regulator of muscle hypertrophy. Originally, although myostatin is recognized to affect to the intracellular signaling such as calcineurin pathway [
IL-15 is also known as a muscle-secreted protein which can regulate muscle mass via inhibiting protein degradation and accelerating differentiation [
SPARC is a cancer preventive protein secreted by skeletal muscle
We recently tried to identify novel muscle-derived proteins that are secreted into the general circulation. The transcriptome of muscle tissue in sedentary and exercised young and old mice were compared. In total, 381 genes in gastrocnemius muscle were up-regulated in mice that exercised for 4 weeks compared with sedentary mice; on the other hand, 100 genes were downregulated in 24-month-old sedentary mice compared with 3-month-old sedentary mice [
A number of epidemiological studies have focused on the relationships between the average individual’s level of physical activity and the incidence of cancer in Europe, the United States, and Japan. The general consensus among the authors of these studies is that physical activity can prevent cancer in the colon, breast, uterus, pancreas, and lungs [
SPARC is a matricellular protein that is primarily involved in development, remodeling, and tissue repair through modulation of cell-cell and cell-matrix interactions [
A cause of ACF formation is dysregulation of apoptosis [
Prospective
Many studies have suggested that there are muscle-secreted proteins yet to be identified. For example, a bioinformatics study showed that the secretome of human muscle cells includes more than 300 proteins [
It is well-known from previous studies that exercise releases various metabolic factors from skeletal muscle into circulation. For example, lactate is generated from carbohydrates via glycolytic metabolism and the amount is based on the intensity of exercise. After its release into blood, lactate is carried to other tissues and is utilized as a substrate of aerobic metabolism or gluconeogenesis. Recently, studies into further functions of lactate have shown that exogenous lactate mediates insulin-induced anti-lipolytic effect via G-protein coupled receptor GPR81 located on plasma membrane [
Conclusion
Skeletal muscle secretes several bioactive proteins from within the cell into extracellular fluid. The secretion of several proteins, whose levels increase in response to exercise, can mediate exercise-induced benefits such as metabolic improvement, anti-inflammation, and muscle hypertrophy. We recently found a novel muscle-secreted protein SPARC which may be fundamental for the colon cancer prevention mechanism of regular exercise, demonstrated by various epidemiological studies. Many other proteins, along with c-miRNAs in exosome and metabolites, secreted from muscle have yet to be identified. In the future, the presence and beneficial function of more unknown bioactive factors are expected to be discovered, which strengthens the development of sports science.
Acknowledgments
This work was supported by Grants-in-Aid from the Japan Society for the Promotion of Science (23700776W.A.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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