SOCE Is Important for Maintaining Sarcoplasmic Calcium Content and Release in Skeletal Muscle Fibers

Abstract

Store-operated Ca entry (SOCE) is a Ca-entry process activated by the depletion of intracellular stores and has an important role in many cell types. In skeletal muscle, however, its role during physiological muscle activation has been controversial. To address this question, sarcoplasmic reticulum (SR) calcium release in a mouse strain with a naturally occurring mutation in the myostatin gene (Compact (Cmpt)) leading to a hypermuscular yet reduced muscle-force phenotype was compared to that in wild-type mice. To elicit Ca release from the SR of flexor digitorum brevis (FDB) fibers, either a ryanodine receptor agonist (4-chloro-meta-cresol) or depolarizing pulses were used. In muscles from Cmpt mice, endogenous protein levels of STIM1 and Orai1 were reduced, and consequently, SOCE after 4-chloro-meta-cresol-induced store depletion was suppressed. Although the voltage dependence of SR calcium release was not statistically different between wild-type and Cmpt fibers, the amount of releasable calcium was significantly reduced in the latter, indicating a smaller SR content. To assess the immediate role of SOCE in replenishing the SR calcium store, the evolution of intracellular calcium concentration during a train of long-lasting depolarizations to a maximally activating voltage was monitored. Cmpt mice exhibited a faster decline in calcium release, suggesting a compromised ability to refill the SR. A simple model that incorporates a reduced SOCE as an important partner in regulating immediate calcium influx through the surface membrane readily accounts for the steady-state reduction in SR calcium content and its more pronounced decline after calcium release.

ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain

“…; Sztretye et al . ), but unexpectedly Orai1‐deficient mice had no endurance deficit (Carrell et al . ).…”

“…A recent study reported that SOCE is activated after every action potential in skinned fast twitch rat muscle fibres, suggesting that SOCE acts as a counter-flux to T-system Ca 2+ extrusion to maintain Ca 2+ homeostasis during muscle contraction (Koenig et al 2018). Several studies reported an increased muscle fatigue in the absence of SOCE, linked to faster decline in Ca 2+ content upon repetitive membrane depolarizations (Stiber et al 2008;Wei-Lapierre et al 2013;Sztretye et al 2017), but unexpectedly Orai1-deficient mice had no endurance deficit (Carrell et al 2016). SOCE is clearly important for skeletal muscle function in humans, because gain-of-function mutations in the ORAI1 gene are causally related to TAM, a muscular disease with elevated blood CK levels and loss of fast twitch (type II) fibres caused by Ca 2+ overload (Rosenberg et al 1985;Bohm et al 2013).…”

Improved Tetanic Force and Mitochondrial Calcium Homeostasis by Astaxanthin Treatment in Mouse Skeletal Muscle

“…was used to fit the time course of the changes of the maximal F/F 0 .This then enabled the estimation of SR calcium content as described in our earlier report [49]. In the equation above x is the number of tetanic pulses applied, b is the time constant of SR calcium depletion, a is the remaining calcium in the SR following the last depolarizing pulse and y 0 is the difference between the total and the remaining SR calcium content following the 8th tetanic pulse.…”

The Complex Role of Store Operated Calcium Entry Pathways and Related Proteins in the Function of Cardiac, Skeletal and Vascular Smooth Muscle Cells

“…Therefore, SOCE likely participates in the muscle contractions during tetanic stimulations in vigorous exercise and fatigue as well as under usual conditions where a contraction might need to be sustained for a long period (Allen et al, 2008 ). Nevertheless, a recent study suggested that SOCE has a role in maintaining and refilling SR Ca 2+ stores, not only in repetitive tetanic stimulation, but also on an immediate basis (Sztretye et al, 2017 ).…”

“…Recently, mice lacking of myostatin gene, which negatively regulates skeletal muscle growth and mass, exhibit reduced STIM1 and Orai1 expression compared to wild type mice. The lower expression of STIM1 and Orai1 in these mice is accompanied by a reduction in SOCE, SR Ca 2+ content and depolarization-evoked Ca 2+ release (Sztretye et al, 2017 ).…”