Mechanisms Underlying Skeletal Muscle Weakness in Human Heart Failure Alterations in Single Fiber Myosin Protein Content and Function

Background-Patients with chronic heart failure (HF) frequently experience skeletal muscle weakness that limits physical function. The mechanisms underlying muscle weakness, however, have not been clearly defined. Methods and Results-This study examined the hypothesis that HF promotes a loss of myosin protein from single skeletal muscle fibers, which in turn reduces contractile performance. Ten patients with chronic HF and 10 controls were studied. Muscle atrophy was not evident in patients, and groups displayed similar physical activity levels, suggesting that observed differences reflect the effects of HF and not muscle atrophy or disuse. In single muscle fibers, patients with HF showed reduced myosin heavy chain protein content (P < 0.05) that manifested as a reduction in functional myosin-actin cross-bridges (P < 0.05). No evidence was found for a generalized loss of myofilament protein, suggesting a selective loss of myosin. Accordingly, single muscle fiber maximal Ca2+ -activated tension was reduced in myosin heavy chain I fibers in patients (P < 0.05). However, tension was maintained in myosin heavy chain IIA fibers in patients because a greater proportion of available myosin heads were bound to actin during Ca2+ activation (P < 0.01). Conclusions-Collectively, our results show that HF alters the quantity and functionality of the myosin molecule in skeletal muscle, leading to reduced tension in myosin heavy chain I fibers. Loss of single fiber myosin protein content represents a potential molecular mechanism underlying muscle weakness and exercise limitation in patients with HF. (Circ Heart Fail. 2009; 2: 700-706.)