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

Cells. 2021 Oct 12;10(10):2722. doi: 10.3390/cells10102722.


Intracellular Ca2+ ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca2+ homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca2+ entry (SOCE), a Ca2+-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 Ca2+ homeostasis in muscle fibers. It is coordinated by STIM1, the main Ca2+ sensor located in the sarcoplasmic reticulum, and ORAI1 protein, a Ca2+-permeable channel located on transverse tubules. It is commonly accepted that Ca2+ 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 Ca2+ 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.

Keywords: Orai1; SOCE-related skeletal muscle diseases; STIM1; skeletal muscle; store-operated calcium entry (SOCE).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Calcium / metabolism*
  • Humans
  • Models, Biological
  • Muscle, Skeletal / metabolism*
  • Muscular Diseases / genetics*
  • Muscular Diseases / therapy
  • ORAI1 Protein / metabolism*
  • Stromal Interaction Molecule 1 / metabolism*


  • ORAI1 Protein
  • Stromal Interaction Molecule 1
  • Calcium