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During exercise, defects in calcium (Ca 2؉ ) release have been proposed to impair muscle function. Here, we show that during exercise in mice and humans, the major Ca 2؉ release channel required for excitationcontraction coupling (ECC) in skeletal muscle, the ryanodine receptor (RyR1), is progressively PKA-hyperphosphorylated, S-nitrosylated, and depleted of the phosphodiesterase PDE4D3 and the RyR1 stabilizing subunit calstabin1 (FKBP12), resulting in ''leaky'' channels that cause decreased exercise tolerance in mice. Mice with skeletal musclespecific calstabin1 deletion or PDE4D deficiency exhibited significantly impaired exercise capacity. A small molecule (S107) that prevents depletion of calstabin1 from the RyR1 complex improved force generation and exercise capacity, reduced Ca 2؉ -dependent neutral protease calpain activity and plasma creatine kinase levels. Taken together, these data suggest a possible mechanism by which Ca 2؉ leak via calstabin1-depleted RyR1 channels leads to defective Ca 2؉ signaling, muscle damage, and impaired exercise capacity. muscle fatigue ͉ calcium channel ͉ calstabin ͉ exitation-contraction coupling ͉ rycals

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