SKELETAL MUSCLE CONTRACTILE DYSFUNCTION IN HEART FAILURE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 慢性心力衰竭的特点是骨骼肌功能的变化，导致身体残疾。我们在这些研究中的具体目标是表征心力衰竭患者的单个骨骼肌纤维功能，目的是确定收缩功能障碍的细胞和分子机制。这些研究的结果将涉及以下目的和假设： 目的1：研究心力衰竭对化学剥皮的人单根骨骼肌纤维收缩特性的影响。 假设：与来自健康对照的纤维相比，来自心力衰竭患者的单根纤维将表现出单位横截面积的力产生减少，缩短速度没有差异。减少的力产生将通过减少的粗丝含量和肌球蛋白重链（MHC）蛋白含量来解释。 目标二：为了检查心力衰竭患者中肌肉废用在收缩功能障碍中的作用，将在心力衰竭患者和残疾对照（即COPD患者）之间比较单纤维功能、粗丝密度和MHC蛋白含量。此外，这些变量将在心力衰竭患者对抗肌肉废用与阻力运动训练之前和之后进行测量。 假设：减少单纤维力的产生和肌原纤维蛋白含量的改变不是由于肌肉废用。与残疾对照组相比，心力衰竭患者中以每纤维横截面积表示的单纤维力产生将减少，这将通过减少的粗丝含量和MHC蛋白质含量来解释。类似地，尽管阻力训练会增加心力衰竭患者由于纤维肥大而产生的绝对力，但它不会纠正单位横截面积的单纤维力产生、粗丝含量或MHC蛋白含量的不足。 目标3：为了研究骨骼肌生长因子表达对心力衰竭中MHC表型的影响，我们将通过测量心力衰竭患者和健康对照者在抗阻运动训练方案前后骨骼肌MHC和胰岛素样生长因子-I（IGF-I）的表达来研究骨骼肌基因表达对合成代谢刺激的反应。 假设：心力衰竭患者将表现出对阻力训练的合成代谢反应受损。与对照组相比，心力衰竭患者骨骼肌MHC和IGF-I mRNA表达的增加在抗阻训练中会减弱。

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.