Understanding the Matrix: Regulation of the Human Muscle Extra Cellular Matrix

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Aging is associated with a greater decline in muscle strength than in size resulting in a lower muscle quality and diminished physical function. This combined decline in muscle size and quality is also mechanistically linked to impairments in whole body metabolism. Currently, the best available intervention to improve muscle size and quality is resistance exercise training. Unfortunately, the anabolic effects of resistance training are blunted in older adults making this form of exercise less effective at increasing muscle size in older men and women. The long-term goals of my research program are: 1) To understand the molecular mechanisms behind age-related loss of muscle size, function and quality in each sex. 2) Target identified mechanisms with exercise and nutritional interventions to maintain or improve muscle size, function and quality in older men and women. Muscle fibers are surrounded by an extra cellular matrix (ECM) comprised primarily of collagen fibers, along with cells that regulate its composition such as Fibro-Adipogenic Progenitors (FAP) cells. Recent work in animal models has shown that ECM properties regulate how force is transferred laterally between muscle fibers and may explain age related difference in muscle quality. Other studies of, muscle damage and regeneration in animals demonstrate that ECM properties and FAP cell function alter the response to anabolic stimuli. These observations suggest that in humans the properties of the ECM may partially explain age related differences in muscle quality and the adaptive response to exercise. However, little is known about these mechanisms in human models of aging and resistance exercise. The short-term goals of my research proposals will address these knowledge gaps while considering possible sex differences. Specifically: 1) Determine the nutritional regulators of ECM turnover following exercise. 2) Understand the effect of human aging on ECM composition and regulators. 3) Identify sex differences in the turnover of contractile and ECM proteins following resistance exercise in older adults. 4) Examine how advanced age regulates the turnover of the ECM following acute resistance exercise. 5) Determine how aging alters ECM properties and regulators following chronic resistance exercise training. These goals will be accomplished using methods in which I have developed significant expertise; such as stable isotope-based measures of protein turnover, measures of gene and protein abundance, and immunohistochemistry. In order to meet these goals, I have developed a plan to recruit and train a diverse team of HQP who will gain skills in human exercise research and a number of cutting-edge molecular techniques. The proposed program of research will lead to a better understanding of how age, sex, exercise and nutrition regulate the composition and function of the human muscle ECM and is part of a longer-term drive to understand the fundamental mechanism of human muscle aging.