Abstract
Store-operated Ca2+ entry (SOCE), a ubiquitous mechanism that allows recovery of Ca2+ ions from the extracellular space, has been proposed to limit fatigue during repetitive skeletal muscle activity. However, the subcellular location for SOCE in muscle fibers has not been unequivocally identified. Here we show that exercise drives a significant remodeling of the sarcotubular system to form previously unidentified junctions between the sarcoplasmic reticulum (SR) and transverse-tubules (TTs). We also demonstrate that these new SR-TT junctions contain the molecular machinery that mediate SOCE: stromal interaction molecule-1 (STIM1), which functions as the SR Ca2+ sensor, and Orai1, the Ca2+-permeable channel in the TT. In addition, EDL muscles isolated from exercised mice exhibit an increased capability of maintaining contractile force during repetitive stimulation in the presence of 2.5 mM extracellular Ca2+, compared to muscles from control mice. This functional difference is significantly reduced by either replacement of extracellular Ca2+ with Mg2+ or the addition of SOCE inhibitors (BTP-2 and 2-APB). We propose that the new SR-TT junctions formed during exercise, and that contain STIM1 and Orai1, function as Ca2+Entry Units (CEUs), structures that provide a pathway to rapidly recover Ca2+ ions from the extracellular space during repetitive muscle activity.
Highlights
Store-operated Ca2+ entry (SOCE) is a ubiquitous Ca2+ entry mechanism, first described in non-excitable cells, that is triggered by depletion of intracellular Ca2+ stores[1,2]
These studies suggest that rapid SOCE in the transverse tubules (TTs) system might involve stromal interaction molecule-1 (STIM1)-Orai[1] coupling within the pre-formed sarcoplasmic reticulum (SR)-TT junctions of the triad, sites of excitation-contraction (EC) coupling known as Ca2+ release units (CRUs)[33,34]
The importance of this process for muscle function is supported by prior studies demonstrating a potential role for SOCE in muscle fatigue[17,18,40], ageing[19,20,41], and myopathy[23,24,27,28,29]
Summary
Store-operated Ca2+ entry (SOCE) is a ubiquitous Ca2+ entry mechanism, first described in non-excitable cells, that is triggered by depletion of intracellular Ca2+ stores (endoplasmic/sarcoplasmic reticulum, respectively ER and SR)[1,2]. Experiments in skinned skeletal muscle fibers have provided evidence that SOCE channels are present in transverse tubules (TTs), specialized invaginations of the PM that propagate the action potential into the fiber interior, and activate rapidly following SR Ca2+ store depletion[12,32] These studies suggest that rapid SOCE in the TT system might involve STIM1-Orai[1] coupling within the pre-formed SR-TT junctions of the triad, sites of excitation-contraction (EC) coupling known as Ca2+ release units (CRUs)[33,34]. Our results show that exercise drives a significant remodeling of the sarcotubular system within the I band of the sarcomere that results in the formation of previously unidentified junctions between the SR and TTs that contain STIM1 and Orai[1] proteins This remodeling is accompanied by an increased resistance to fatigue during repetitive high frequency stimulation that is significantly reduced by preventing Ca2+ influx following either removal of extracellular Ca2+ or addition of SOCE inhibitors
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