Orai1-dependent calcium entry promotes skeletal muscle growth and limits fatigue

Store-operated Ca²⁺ entry (SOCE) in skeletal muscle involves signalling between stromal-interacting molecule 1 (STIM1) in the sarcoplasmic reticulum (SR) and Ca²⁺ selective Orai1 channels in the sarcolemma. Here we generate transgenic mice with muscle-specific expression of dominant-negative Orai1 (dnOrai1) and demonstrate that Orai1-dependent SOCE promotes growth and limits fatigue in adult skeletal muscle. dnOrai1 mice lack SOCE specifically in muscle but are fertile and thrive well into adulthood. Although muscle ultrastructure, excitation-contraction (EC) coupling, fibre type, and expression of other Ca²⁺ regulatory proteins are unaltered, dnOrai1 mice exhibit reduced body weight, muscle mass and fibre cross-sectional area. Importantly, during intense repetitive activity, dnOrai1 mice display increased susceptibility to fatigue at the single fibre, excised muscle and whole-animal levels. We further show that STIM1 and Orai1 proteins co-localize within the triad junction but do not exist in a preassembled context. These results show that Orai1-dependent SOCE has an important physiological role in muscles of adult mice.