This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chronic heart failure is characterized by changes in skeletal muscle function that contribute to physical disability. 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. Results from these studies will address the following Aims and Hypotheses:
Aim 1 : To examine the effect of heart failure on the contractile properties of chemically-skinned, human single skeletal muscle fibers. Hypothesis: Single fibers from heart failure patients will exhibit reduced force production per crosssectional area compared to fibers from healthy controls, with no differences in shortening velocity. Reduced force production will be explained by decreased thick filament content and myosin heavy chain (MHC) protein content.
Aim 2 : To examine the role of muscle disuse in contractile dysfunction in heart failure patients, single fiber function, thick filament density and MHC protein content will be compared between heart failure patients and disabled controls (i.e. COPD patients). In addition, these variables will be measured in heart failure patients before and after countering muscle disuse with resistance exercise training. Hypothesis: Reduced single fiber force production and alterations in myofibrillar protein content are not due to muscle disuse. Single fiber force production expressed per fiber cross-sectional area will be reduced in heart failure patients compared to disabled controls and this will be explained by reduced thick filament content and MHC protein content. Similarly, although resistance training will increase absolute force production in heart failure patients due to fiber hypertrophy, it will not correct deficits in single fiber force production per cross-sectional area, thick filament content or MHC protein content.
Aim 3 : To examine the effect of skeletal muscle growth factor expression on MHC phenotype in heart failure, we will examine the response of skeletal muscle gene expression to an anabolic stimulus by measuring skeletal muscle MHC and insulin-like growth factor-I (IGF-I) expression in heart failure patients and healthy controls before and after a resistance exercise training regimen. Hypothesis: Heart failure patients will demonstrate an impaired anabolic response to resistance training. The increase in skeletal muscle MHC and IGF-I mRNA expression with resistance training will be blunted in heart failure patients compared to controls.
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