Skeletal muscle contractile dysfunction in heart failure

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DESCRIPTION (provided by applicant): Alterations in skeletal muscle contribute to physical disability in patients with chronic heart failure by reducing their capacity for physical work. Skeletal muscle function is determined, in large part, by the energetic and mechanical properties of its individual fibers. Although numerous studies have identified defects in skeletal muscle oxidative capacity and mitochondrial function, no study has examined the effect of heart failure on the mechanical properties of skeletal muscle. We propose that changes in the fundamental contractile properties of skeletal muscle (i.e., force and velocity) contribute to reduced muscle function and physical disability in heart failure patients. Our specific objective in these studies is to characterize single skeletal muscle fiber function in heart failure patients with the goal of defining the cellular and molecular mechanisms underlying contractile dysfunction. We hypothesize that: 1) heart failure impairs single fiber function by reducing myosin heavy chain (MHC) protein and thick filament content; 2) alterations in single muscle fiber function, protein content and ultrastructure are not related to muscle disuse; and 3) reduced MHC protein content and shifts in isoform distribution are explained by altered patterns of gene expression secondary to reduced skeletal muscle growth factor expression. To test our hypotheses, we will measure contractile performance, myofibrillar protein expression and myofibrillar structure in single skeletal muscle fibers obtained from heart failure patients, age-matched, non-diseased, sedentary controls and disabled controls. These measurements, together with assessment of skeletal muscle gene expression, will also be conducted in heart failure patients and healthy controls before and after a 4 month resistance exercise training program. Results from these studies will provide a comprehensive understanding of the mechanisms underlying skeletal muscle contractile dysfunction in heart failure as it pertains to the structural and functional remodeling of the contractile machinery. Our findings will also provide information regarding the utility of resistance exercise training to improve single muscle fiber function, as well as whole muscle performance and whole body physical function in heart failure patients.