SKELETAL MUSCLE CONTRACTILE DYSFUNCTION IN HEART FAILURE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 慢性心力衰竭的特征是骨骼肌功能的改变，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标和假设： 目的1：研究心力衰竭对化学剥离的人单个骨骼肌纤维收缩特性的影响。 假设：与健康对照组的纤维相比，心力衰竭患者的单个纤维的每横截面积的作用力将减少，缩短速度没有差异。粗丝含量和肌球蛋白重链(MHC)蛋白含量的降低将解释力量产生的减少。 目的：比较心力衰竭患者和残疾对照组(即COPD患者)的单纤维功能、粗丝密度和MHC蛋白含量，探讨肌肉废用在心力衰竭患者收缩功能障碍中的作用。此外，还将对心力衰竭患者在抵抗运动训练对抗肌肉停用前后的这些变量进行测量。 假设：单一纤维力的减少和肌原纤维蛋白含量的改变不是由于肌肉的停用。与残疾对照组相比，心力衰竭患者单位纤维横截面积上的单纤维力产生将减少，这将由粗丝含量和MHC蛋白质含量的减少来解释。同样，尽管阻力训练将增加因纤维肥大而导致的心力衰竭患者的绝对力产生，但它不会纠正单位横截面单纤维力产生、粗丝含量或MHC蛋白质含量的不足。 目的：通过检测抗阻运动训练前后心力衰竭患者和健康对照组骨骼肌MHC和胰岛素样生长因子-I(IGF-I)的表达，探讨骨骼肌生长因子表达对心力衰竭患者MHC表型的影响。 假设：心力衰竭患者会表现出对阻力训练的合成代谢反应受损。与对照组相比，阻力训练后心力衰竭患者骨骼肌MHC和IGF-I基因表达的增加将变得迟钝。

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.