Skeletal muscle molecular alterations precede whole-muscle dysfunction in NYHA Class II heart failure patients.
Skeletal muscle molecular alterations precede whole-muscle dysfunction in NYHA Class II heart failure patients.
复制标题
NYHA II 级心力衰竭患者的骨骼肌分子改变先于全肌肉功能障碍。
DOI：
10.2147/cia.s37879
复制
发表时间：
2012
影响因子：
3.6
通讯作者：
Delafontaine P
中科院分区：
文献类型：
--
作者：
Godard MP;Whitman SA;Song YH;Delafontaine P
心力衰竭(HF)是一种在越来越多的成年人中造成衰弱的疾病，它会在心肌和骨骼肌中产生结构和神经激素的变化。然而，这些改变及其影响的分子途径仍然没有明确的特征。已知疾病进展通过未知的机制改变骨骼肌纤维组成。此外，特定的激素途径，包括那些涉及骨骼肌胰岛素样生长因子-1(IGF-1)和胰岛素样生长因子结合蛋白-5(IGFB-5)的途径似乎发生了扰动，可能影响肌肉的新陈代谢和再生。我们假设IGF-1和IGFB-5mRNA水平的变化与单个骨骼肌纤维肌球蛋白重链亚型在疾病进展早期的转化相关，使这些分子成为心力衰竭时骨骼肌变化的有价值的标志物。为了研究心力衰竭患者“早期”事件中的这些分子，我们从纽约心脏协会(NYHA)II级心力衰竭患者和对照的骨骼肌活检中获得了单纤维的分子分析，并对等长力量和肌肉大小进行了量化。与对照组(13%±2%)相比，心力衰竭组(30%±7%)有更多(P<；0.05)单条肌纤维同时表达两条或两条以上肌球蛋白重链。胰岛素样生长因子-1和胰岛素样生长因子结合蛋白-5在心力衰竭患者中的表达分别是对照组的5倍和15倍(P<；0.05)。值得注意的是，IGF-1的表达与肌肉横截面积相关(P<；0.05)，导致HF患者的整体肌肉质量下降(P<；0.05)，尽管等长力量或整体肌肉大小没有明显下降。这些数据表明，肌球蛋白重链亚型、IGF-1和IGFB-5水平的分子变化先于先前与心力衰竭相关的大体形态和功能缺陷，并可用于预测患者的功能结果。
Heart failure (HF), a debilitating disease in a growing number of adults, exerts structural and neurohormonal changes in both cardiac and skeletal muscles. However, these alterations and their affected molecular pathways remain uncharacterized. Disease progression is known to transform skeletal muscle fiber composition by unknown mechanisms. In addition, perturbation of specific hormonal pathways, including those involving skeletal muscle insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-5 (IGFB-5) appears to occur, likely affecting muscle metabolism and regeneration. We hypothesized that changes in IGF-1 and IGFB-5 mRNA levels correlate with the transformation of single–skeletal muscle fiber myosin heavy chain isoforms early in disease progression, making these molecules valuable markers of skeletal muscle changes in heart failure. To investigate these molecules during “early” events in HF patients, we obtained skeletal muscle biopsies from New York Heart Association (NYHA) Class II HF patients and controls for molecular analyses of single fibers, and we also quantified isometric strength and muscle size. There were more (P < 0.05) single muscle fibers coexpressing two or more myosin heavy chains in the HF patients (30% ± 7%) compared to the control subjects (13% ± 2%). IGF-1 and IGFBP-5 expression was fivefold and 15-fold lower in patients with in HF compared to control subjects (P < 0.05), respectively. Strikingly, there was a correlation in IGF-1 expression and muscle cross-sectional area (P < 0.05) resulting in a decrease in whole-muscle quality (P < 0.05) in the HF patients, despite no significant decrease in isometric strength or whole-muscle size. These data indicate that molecular alterations in myosin heavy chain isoforms, IGF-1, and IGFB-5 levels precede the gross morphological and functional deficits that have previously been associated with HF, and may be used as a predictor of functional outcome in patients.