Protein modification and the aging phenotype of human skeletal muscle

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Project Summary Age-related reductions in muscle contractile performance are mediated by reductions in muscle size (atrophy) and alterations in actin-myosin cross bridge function that are independent of size. Together, they contribute to sarcopenia, the age-related loss of skeletal muscle mass and function. A hallmark of sarcopenia is the loss of contractile power (= product of force and velocity) which, in turn, predicts physical dysfunction, and mobility disability. Importantly, contractile power declines earlier in life and more precipitously than reductions in contractile force or muscle size, thereby suggesting that power is subject to the influence of unique mechanisms. During repeated contractions of high velocity, muscle fatigability is also increased with age, such that older, healthy adults experience a much greater reduction in muscular power over the course of a single bout of repeated voluntary contractions. In combination, these aspects of muscle aging leave older adults at greater risk of falls and physical impairments during repetitious activities (stair climbing, walking etc.). Somewhat paradoxically, muscle tension (force per unit cross sectional area) has been shown to increase with age when contractile velocity is zero (isometric). Similarly, older adults are less fatigable during isometric contractions. This constellation of poorly understood functional characteristics defines an Aging Phenotype of skeletal muscle whose mechanisms may reveal important targets for intervention for improving physical function in older adults with sarcopenia. We propose that alterations in cross-bridge level biology in the aging sarcomere contribute to velocity-dependent contractile dysfunction and will perform experiments in human skeletal muscle to test the hypothesis that the sarcomeric protein Myosin Binding Protein C (MyBP-C) is central to this phenomenon. MyBP-C is a regulatory protein located near the center of the sarcomere, known to modulate myocardial contractility via phosphorylation-dependent interactions with the thin and thick filaments. While skeletal and cardiac isoforms of MyBP-C are highly conserved and share structural and sequence homology, it is not clear whether MyBP-C has similar phosphorylation-dependent influences on skeletal muscle contractility. Recent pre-clinical studies suggest skeletal MyBP-C phosphorylation influences contractile force and velocity, and age and fatiguing contractions alter phosphorylation differentially. Our studies in isolated human single muscle fibers will translate pre-clinical evidence to humans and allow us to interrogate the influence of MyBP-C on age and fatigue-related changes in skeletal muscle contractility. We will identify post translational modifications to sarcomeric proteins with age and fatigue while screening for other candidates of interest within the human muscle cell. These studies will reveal important information regarding the poorly understood Aging Phenotype of Skeletal Muscle while establishing foundational data supporting the pursuit of molecular targets for interventions with the goal of improving clinical outcomes in older adults.