Role of STIM1/ORAI1-mediated store-operated Ca2+ entry in skeletal muscle physiology and disease

• Published in: Cell calcium (Edinburgh) 2018-12, Vol.76, p.101-115
• Main Authors: Michelucci, Antonio, García-Castañeda, Maricela, Boncompagni, Simona, Dirksen, Robert T.
• Format: Article
• Language: English
• Subjects: Ca2+ signaling; Ca2+-release-activated-Ca2+ (CRAC); Muscle fatigue; Tubular aggregate myopathy (TAM)
• ISSN: 0143-4160; 1532-1991
• DOI: 10.1016/j.ceca.2018.10.004

[Display omitted] •STIM1 and ORAI1 coordinate SOCE in skeletal muscle.•STIM1/ORAI1 SOCE promotes muscle development/growth and Ca2+ store content during periods of prolonged stimulation.•Loss-of-Function and Gain-of-Function mutations in STIM1 and ORAI1 result in disorders with myopathy.•STIM/ORAI1 SOCE dysfunction contributes to the pathogenesis of other muscle-related disorders.•Tight regulation of STIM1/ORAI1 SOCE is critical for optimal skeletal muscle function. Store-operated Ca2+ entry (SOCE) is a Ca2+ entry mechanism activated by depletion of intracellular Ca2+ stores. In skeletal muscle, SOCE is mediated by an interaction between stromal-interacting molecule-1 (STIM1), the Ca2+ sensor of the sarcoplasmic reticulum, and ORAI1, the Ca2+-release-activated-Ca2+ (CRAC) channel located in the transverse tubule membrane. This review focuses on the molecular mechanisms and physiological role of SOCE in skeletal muscle, as well as how alterations in STIM1/ORAI1-mediated SOCE contribute to muscle disease. Recent evidence indicates that SOCE plays an important role in both muscle development/growth and fatigue. The importance of SOCE in muscle is further underscored by the discovery that loss- and gain-of-function mutations in STIM1 and ORAI1 result in an eclectic array of disorders with clinical myopathy as central defining component. Despite differences in clinical phenotype, all STIM1/ORAI1 gain-of-function mutations-linked myopathies are characterized by the abnormal accumulation of intracellular membranes, known as tubular aggregates. Finally, dysfunctional STIM1/ORAI1-mediated SOCE also contributes to the pathogenesis of muscular dystrophy, malignant hyperthermia, and sarcopenia. The picture to emerge is that tight regulation of STIM1/ORAI1-dependent Ca2+ signaling is critical for optimal skeletal muscle development/function such that either aberrant increases or decreases in SOCE activity result in muscle dysfunction.