Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond

Intracellular Ca(2+) ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca(2+) homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca(2+) entry (SOCE), a Ca(2+)-entry process activated by depletion of intracellular stores contributing to the regulation of various function in many cell types, is pivotal to ensure a proper Ca(2+) homeostasis in muscle fibers. It is coordinated by STIM1, the main Ca(2+) sensor located in the sarcoplasmic reticulum, and ORAI1 protein, a Ca(2+)-permeable channel located on transverse tubules. It is commonly accepted that Ca(2+) entry via SOCE has the crucial role in short- and long-term muscle function, regulating and adapting many cellular processes including muscle contractility, postnatal development, myofiber phenotype and plasticity. Lack or mutations of STIM1 and/or Orai1 and the consequent SOCE alteration have been associated with serious consequences for muscle function. Importantly, evidence suggests that SOCE alteration can trigger a change of intracellular Ca(2+) signaling in skeletal muscle, participating in the pathogenesis of different progressive muscle diseases such as tubular aggregate myopathy, muscular dystrophy, cachexia, and sarcopenia. This review provides a brief overview of the molecular mechanisms underlying STIM1/Orai1-dependent SOCE in skeletal muscle, focusing on how SOCE alteration could contribute to skeletal muscle wasting disorders and on how SOCE components could represent pharmacological targets with high therapeutic potential.