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Background  Exercise intolerance in chronic heart failure (HF) has been attributed to abnormalities of the skeletal muscles. Muscle function depends on intact excitation-contraction coupling (ECC), but ECC studies in HF models have been inconclusive, due to deficiencies in the animal models and tools used to measure calcium (Ca 2+ ) release, mandating investigations in skeletal muscle from HF patients. The purpose of this study was to test the hypothesis that Ca 2+  release is significantly impaired in the skeletal muscle of HF patients in whom exercise capacity is severely diminished compared to age-matched healthy volunteers.    Methods and Findings  Using state-of-the-art electrophysiological and optical techniques in single muscle fibers from biopsies of the locomotive  vastus lateralis  muscle, we measured the action potential (AP)-evoked Ca 2+  release in 4 HF patients and 4 age-matched healthy controls. The mean peak Ca 2+  release flux in fibers obtained from HF patients (10±1.2 µM/ms) was markedly (2.6-fold) and significantly (p<0.05) smaller than in fibers from healthy volunteers (28±3.3 µM/ms). This impairment in AP-evoked Ca 2+  release was ubiquitous and was not explained by differences in the excitability mechanisms since single APs were indistinguishable between HF patients and healthy volunteers.    Conclusions  These findings prove the feasibility of performing electrophysiological experiments in single fibers from human skeletal muscle, and offer a new approach for investigations of myopathies due to HF and other diseases. Importantly, we have demonstrated that one step in the ECC process, AP-evoked Ca 2+  release, is impaired in single muscle fibers in HF patients.

Action Potential-Evoked Calcium Release Is Impaired in Single Skeletal Muscle Fibers from Heart Failure Patients