Mechanisms of human skeletal muscle disuse atrophy

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Skeletal muscle is a unique tissue with a tremendous capacity to modify its size and functional characteristics in response to changes in physical activity. Periods of sedentary behavior and muscle disuse (e.g., due to limb casting or bed rest) lead to a decline in skeletal muscle mass, also known as “disuse muscle atrophy”. Muscle atrophy is a non-pathological event characterized by a reduction in muscle fibre size resulting from a loss of muscle protein content. Muscle loss will likely affect every person at some point during their lifetime and has negative consequences including reductions in strength, the onset of insulin resistance, and body fat-mass accumulation. Despite these negative consequences, the processes and mechanisms that cause disuse-related muscle atrophy in humans remain unclear. The LONG TERM OBJECTIVE of my research program is to understand the metabolic and molecular regulation of human muscle protein metabolism in response to stimuli that promote skeletal muscle loss (e.g., muscle disuse), maintenance (e.g., physical activity, nutritional intake) and/or growth (e.g., resistance exercise). Over the next five-years, my laboratory will address two short-term research objectives that will contribute to my long-term research objective. The first SHORT-TERM OBJECTIVE is to develop a greater understanding of the metabolic and mechanistic causes of disuse-induced skeletal muscle atrophy in humans. The maintenance of skeletal muscle mass is dependent on the regulated balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Under atrophy conditions, the rate of MPB exceeds the rate of MPS resulting in net loss of muscle protein. However, the contribution of changes in MPS and MPB to disuse atrophy is unknown, and may differ to varying extents at different time-points during disuse and between different muscles in the body. The second SHORT-TERM OBJECTIVE is to identify the metabolic and molecular processes that facilitate skeletal muscle growth in humans. Muscle atrophy can be reversed with physical activity and exercise. Resistance exercise arguably offers the most effective strategy to increase skeletal muscle mass and strength. Muscle growth occurs when MPS exceeds MPB resulting in an increase of muscle proteins, and eventually muscle growth. However, the metabolic and molecular events that promote skeletal muscle growth after disuse have not been explored in humans. The results from this research will enhance our fundamental understanding of the mechanisms responsible for disuse-induced skeletal muscle atrophy, and provide insight into how resistance exercise facilitates muscle growth in previously atrophied and non-atrophied muscle. This knowledge will contribute to the development of effective countermeasures for the prevention and rehabilitation of disuse skeletal muscle atrophy.**********************