Figure 3.

Schematic overview of the physiological role of SOCE in skeletal muscle and pathophysiological consequences of Ca²⁺-influx dysregulation based on mouse-model studies. STIM1-controlled Ca²⁺ influx, either through Orai1 or TRPC channels, ought to be tightly regulated for proper muscle development and function. STIM1-gated Orai1-mediated Ca²⁺ influx seems to be a requisite for proper Ca²⁺ homeostasis in the skeletal muscle, maintaining resting cytosolic [Ca²⁺] sufficiently high and adequately filling the SR Ca²⁺ stores. This constitutes an essential mechanism that compensates for Ca²⁺ losses to the extracellular space. Importantly, these phenomena may not only act during periods of intense stimulation, but may also be required during basal conditions and regular muscle function. On the one hand, suppressing Ca²⁺ influx, for example in STIM1-deficient muscle fibers, leads to improper muscle development and function. This is likely due to hampered activation of NFAT-dependent signaling and defective expression of Ca²⁺-handling proteins, such as SERCAs and RyRs, as well as other proteins involved in muscle contraction. On the other hand, events such as mutations in dystrophin or overexpression of TRPC channels, lead to muscle dystrophy and degeneration, likely due to mitochondrial Ca²⁺ overload and Ca²⁺-dependent activation of the apoptotic program. Abbreviations: NFAT, nuclear factor of activated T cells; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic-reticulum Ca²⁺-ATPase; SR, sacroplasmic reticulum; STIM, stromal interaction molecule; TRPC, canonical transient receptor potential.