Abstract
Calcium is a crucial mediator of cell signaling in skeletal muscles for basic cellular functions and specific functions, including contraction, fiber-type differentiation and energy production. The sarcoplasmic reticulum (SR) is an organelle that provides a large supply of intracellular Ca2+ in myofibers. Upon excitation, it releases Ca2+ into the cytosol, inducing contraction of myofibrils. During relaxation, it takes up cytosolic Ca2+ to terminate the contraction. During exercise, Ca2+ is cycled between the cytosol and the SR through a system by which the Ca2+ pool in the SR is restored by uptake of extracellular Ca2+ via a specific channel on the plasma membrane. This channel is called the store-operated Ca2+ channel or the Ca2+ release-activated Ca2+ channel. It is activated by depletion of the Ca2+ store in the SR by coordination of two main molecules: stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (ORAI1). Recently, myopathies with a dominant mutation in these genes have been reported and the pathogenic mechanism of such diseases have been proposed. This review overviews the calcium signaling in skeletal muscles and role of store-operated Ca2+ entry in calcium homeostasis. Finally, we discuss the phenotypes and the pathomechanism of myopathies caused by mutations in the STIM1 and ORAI1 genes.
Highlights
The main roles of skeletal muscles are to produce the force for the maintenance of the body and for movement, in addition to many other functions
This review discusses the functions of stromal interaction molecule 1 (STIM1) and ORAI1 in store-operated Ca2+ entry (SOCE), the effects of their mutations on Ca2+ homeostasis in skeletal myofibers and the consequent pathomechanism of tubular aggregate myopathy (TAM)
STIM1 is a single transmembrane (TM) protein consisting of 685 amino acids (NP_003147.2) and localized in the sarco/endoplasmic reticulum (SR/ER) (Figure 2A)
Summary
The main roles of skeletal muscles are to produce the force for the maintenance of the body and for movement, in addition to many other functions. Calcium is a major signaling mediator of the force-generating contraction of skeletal muscles [1,2]. The Ca2+ released from the sarcoplasmic reticulum (SR) in response to depolarization of the transverse tubule (T-tubule) membrane by a nerve signal induces sarcomere contraction of myofibrils, a mechanism known as excitation–contraction (EC) coupling [3]. Mutations in genes encoding two major proteins in SOCE, stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (ORAI1), have been identified as a cause of tubular aggregate myopathy (TAM) [8,9,10,11,12,13,14]. This review discusses the functions of STIM1 and ORAI1 in SOCE, the effects of their mutations on Ca2+ homeostasis in skeletal myofibers and the consequent pathomechanism of TAM
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