Role of Store-operated Calcium Entry in Skeletal Muscle

Our group was the first to demonstrate that store-operated Ca²⁺ entry (SOCE) in skeletal muscle cells is coordinated by both STIM1 Ca²⁺ sensors located in the sarcoplasmic reticulum and Ca²⁺-permeable Orai1 channels in the sarcolemma. Using muscle-specific dnOrai1 transgenic mice and muscle-specific Orai1 knockout mice, we demonstrated that SOCE in skeletal muscle promotes skeletal muscle growth and limits muscle fatigue. Importantly, reduced SOCE activity contributes to muscle dysfunction in aging, debilitating myopathies suffered by patients with severe combined immunodeficiency due to loss-of-function mutations in the genes encoding STIM1 and Orai1, and gain-of-function mutations in STIM1 and Orai1 cause Tubular Aggregate Myopathy. Together, these findings demonstrate that SOCE plays a previously unappreciated role in skeletal muscle fatigue and disease and that STIM1-Orai1 coupling represents an exciting and relatively untapped frontier in muscle biology. Current work is focused on determining the muscle-specific mechanisms for STIM1-Orai1 coupling and the role of SOCE dysfunction in muscle disease.

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