Store-operated Ca2+ entry is activated by every action potential in skeletal muscle

Abstract

Store-operated calcium (Ca2+) entry (SOCE) in skeletal muscle is rapidly activated across the tubular system during direct activation of Ca2+ release. The tubular system is the invagination of the plasma membrane that forms junctions with the sarcoplasmic reticulum (SR) where STIM1, Orai1 and ryanodine receptors are found. The physiological activation of SOCE in muscle is not defined, thus clouding its physiological role. Here we show that the magnitude of a phasic tubular system Ca2+ influx is dependent on SR Ca2+ depletion magnitude, and define this as SOCE. Consistent with SOCE, the influx was resistant to nifedipine and BayK8644, and silenced by inhibition of SR Ca2+ release during excitation. The SOCE transient was shaped by action potential frequency and SR Ca2+ pump activity. Our results show that SOCE in skeletal muscle acts as an immediate counter-flux to Ca2+ loss across the tubular system during excitation-contraction coupling.

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

“…; Koenig et al . ). The peculiar architecture of the SR permanently facing the PM might account for the rapid SOCE activation as might the preferential expression of the longer STIM1L splice variant in skeletal muscle (Darbellay 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 . ). 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 .…”

“…The ubiquitous SOCE mechanism mediated by STIM and ORAI proteins has distinctive characteristics in skeletal muscle. SOCE activates within milliseconds in skeletal muscle cells, while the sequence of events linking store depletion to ORAI1 gating typically takes several tens of seconds in other tissues (Launikonis & Rios, 2007;Edwards et al 2010;Koenig et al 2018). The peculiar architecture of the SR permanently facing the PM might account for the rapid SOCE activation as might the preferential expression of the longer STIM1L splice variant in skeletal muscle (Darbellay et al 2011).…”

“…The SR is also more resilient to Ca 2+ depletion due to its high Ca 2+ buffering capacity and the large amount of SERCA pumps (Payne et al 2009), and whether the SR Ca 2+ content decreases sufficiently during physiological muscle activity to stimulate SOCE has been challenged (Cully & Launikonis, 2013). 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).…”

“…As the process of excitation-contraction can occur in the absence of external Ca 2+ , the role of SOCE in this tissue has been overlooked. The situation changed after the report of SOCE in muscle cells (Kurebayashi & Ogawa, 2001), the clarification of its role in maintaining cytosolic Ca 2+ levels during contraction (Koenig et al 2018), and the discovery of the muscular pathologies associated with STIM1 and ORAI1 mutations (Lacruz & Feske, 2015). Gain-of-function mutations in STIM1 and ORAI1 genes are causally associated with tubular aggregate myopathy (TAM), a genetic disorder (MIM no.…”