Orai1-dependent Calcium Entry Promotes Skeletal Muscle Growth and Limits Fatigue

Abstract

Store-operated Ca ²⁺ entry (SOCE) in skeletal muscle involves signaling between stromal interaction molecule 1 (STIM1) in the sarcoplasmic reticulum and Ca ²⁺ 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 coupling fiber type, and expression of other Ca ²⁺ regulatory proteins are unaltered, dnOrai1 mice exhibit reduced body weight, muscle mass, and fiber 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 colocalise 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.