Skeletal muscle contractile dysfunction in heart failure

描述(申请人提供)：骨骼肌的改变通过降低患者的体力工作能力而导致慢性心力衰竭患者的身体残疾。骨骼肌的功能在很大程度上是由其单个纤维的能量和机械特性决定的。虽然许多研究已经发现骨骼肌氧化能力和线粒体功能存在缺陷，但还没有研究探讨心力衰竭对骨骼肌力学特性的影响。我们认为，骨骼肌的基本收缩特性(即力和速度)的变化有助于心力衰竭患者肌肉功能的降低和身体残疾。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。我们假设：1)心力衰竭通过减少肌球蛋白重链(MHC)蛋白和粗丝含量来损害单纤维功能；2)单肌纤维功能、蛋白质含量和超微结构的改变与肌肉停用无关；以及3)MHC蛋白含量减少和异构体分布的改变是由继发于骨骼肌生长因子表达减少的基因表达模式的改变来解释的。为了验证我们的假设，我们将测量心力衰竭患者、年龄匹配的非疾病对照组和残疾对照组的单个骨骼肌纤维的收缩性能、肌原纤维蛋白表达和肌原纤维结构。这些测量以及骨骼肌基因表达的评估也将在心力衰竭患者和健康对照组进行，在4个月的阻力运动训练计划之前和之后进行。这些研究的结果将全面了解心力衰竭时骨骼肌收缩功能障碍的机制，因为它与收缩机械的结构和功能重塑有关。我们的发现还将提供有关阻力运动训练对改善心力衰竭患者的单个肌肉纤维功能以及整体肌肉表现和全身身体功能的效用的信息。

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.