Store-operated Ca²⁺ entry (SOCE), a Ca²⁺ entry mechanism activated by depletion of intracellular stores, is mediated by the coupling between stromal interacting molecule-1 (STIM1), a luminal Ca²⁺ sensor protein in the endoplasmic reticulum (ER) membrane (Roos et al., 2005), and Ca²⁺-permeable Orai1 channels in the plasma membrane (Feske et al., 2006). In skeletal muscle, SOCE is similarly coordinated by a functional interaction between STIM1 in the sarcoplasmic reticulum (SR) and Orai1 in the transverse tubule (TT) (Kurebayashi and Ogawa, 2001; Lyfenko and Dirksen, 2008; Stiber et al., 2008), specialized invaginations of the surface membrane that propagate action potentials to trigger SR Ca²⁺ release during excitation-contraction (EC) coupling. While the precise physiological role(s) of SOCE in muscle remains incompletely defined, SOCE has been proposed to promote myoblast fusion/differentiation (Darbellay et al., 2009) and muscle development (Kurebayashi and Ogawa, 2001; Wei-Lapierre et al., 2013; Carrell et al., 2016), reduce fatigue during periods of prolonged stimulation (Wei-Lapierre et al., 2013; Carrell et al., 2016; Pan et al., 2002; Boncompagni et al., 2017), as well as serve as a counter-flux to Ca²⁺ loss across the TT system during EC coupling (Koenig et al., 2018). Importantly, mutations in the genes that encode STIM1 and Orai1 underlie an array of disorders with clinical myopathy as central defining component. SOCE dysfunction also contributes to the pathogenesis of several other muscle disorders (Michelucci et al., 2018). Thus, SOCE plays an important role in both normal muscle development/function and muscle disease.

In resting mammalian skeletal muscle, STIM1 proteins are found throughout the I band of the sarcomere (Stiber et al., 2008; Wei-Lapierre et al., 2013; Boncompagni et al., 2017). On the other hand, Orai1 channels at rest are found almost exclusively at the A-I band junction, in accordance with their localization within the TT membrane of the triad (Wei-Lapierre et al., 2013; Boncompagni et al., 2017). A modest degree of STIM1-Orai1 co-localization at the A-I band junction at rest has been suggested to explain in part the uniquely rapid activation of SOCE (<1 s) observed in skeletal muscle (Koenig et al., 2018; Launikonis and Ríos, 2007; Edwards et al., 2011). However, STIM1 and Orai1 localization in muscle is not static, as acute treadmill exercise drives a significant reorganization of the sarcotubular membranes in the I band of extensor digitorum longus (EDL) fibers of wild type (WT) mice that involves: i) remodeling of the SR into stacks of flat cisternae; ii) elongation of the TT into the I band; and iii) increased co-localization of Orai1 with STIM1 in the I band (Boncompagni et al., 2017). This exercise-induced remodeling leads to the formation of new SR-TT contacts that are structurally distinct from triad junctions in that they are oriented longitudinally at the I band (while triads are transversally oriented at the A-I band junction) and display a junctional gap of only 7–8 nm (while triads exhibit a 12 nm junctional gap) (Boncompagni et al., 2017). Importantly, the formation of these junctions following acute exercise correlates with an increased resistance to EDL muscle contractile decline during repetitive stimulation in presence of extracellular Ca²⁺, but not under conditions that reduce SOCE (0 Ca², BTP-2, 2-APB) (Boncompagni et al., 2017). As the formation of the SR-TT junctions within the I band following acute exercise are coincident with enhanced STIM1-Orai1 co-localization and force production during sustained activity, these structural elements were suggested to function as Calcium Entry Units (CEUs).

In spite of these findings, the stability of CEUs formed following exercise, process for disassembly of the components, and impact on Orai1-dependent SOCE, Ca²⁺ dynamics, and muscle force production remain unknown. In fact, the precise degree to which CEUs formed after exercise promote SOCE, optimize Ca²⁺ dynamics and contribute to the adaptation of muscle function in response to acute exercise is unknown. Here, we addressed these issues using a combination of structural (electron microscopy, EM) and functional (Mn²⁺ quench of fura-2 fluorescence, intracellular Ca²⁺ measurements, and muscle contractility) approaches in EDL muscle and flexor digitorum brevis (FDB) fibers from WT and Orai1-deficient mice in the absence of exercise (control) or <1, 6, and 24 hr after acute treadmill exercise. Together, the results support the idea that TT association with SR stacks in the I band promotes Orai1-dependent SOCE needed to replenish releasable Ca²⁺ stores, maintain SR Ca²⁺ release, and maximize contractile force during repetitive stimulation of fast twitch skeletal muscle.

We previously reported that acute treadmill exercise drives the formation of contacts between remodeled SR stacks and extensions of the TT at the I band that promote co-localization of STIM1 and Orai1 proteins. The assembly of these new junctions (CEUs) correlates with reduced EDL muscle force decline during repetitive stimulation (Boncompagni et al., 2017). Here, we determined the time course of the disassembly of CEUs following exercise, as well as the impact of these junctions on Orai1-dependent Ca²⁺ entry, myoplasmic Ca²⁺ dynamics, and muscle contractile function. The results, summarized in the model shown in Figure 8, demonstrate that: a) CEUs are dynamic structures that assemble during exercise and disassemble following recovery (Figures 1 and 2); b) TT retraction from the I band following exercise occurs before SR-stack disassembly (Figures 1 and 2); c) peak SOCE activity (i.e. maximum rate of Mn²⁺ quench), reduced Ca²⁺ store content and increased resting Ca²⁺, as well as sustained Ca²⁺ transient amplitude and force production during repetitive stimulation all increase/decrease in parallel with the time course of TT extension within the I band (Figures 3, 5 and 6); d) exercise-induced CEU formation results in constitutively-activated SOCE (Figure 4); and e) increased SOCE activity and sustained force production during repetitive stimulation requires Orai1 channels (Figure 7). Together, these results indicate that the stacks of flat-parallel SR cisternae formed after exercise are functionally competent CEUs only when associated with a TT extended from the triad.

Figure 8

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Two main findings of this study are: a) TTs retract from the CEU following exercise prior to SR-stack disassembly (Figures 1 and 2) and b) exercise-dependent increases in Orai1-mediated SOCE (Figures 3, 4 and 7), intracellular Ca²⁺ dynamics (Figure 5), and maintained contractile activity during repetitive stimulation (Figure 6) declines with a time course like that of TT retraction. Together, these results show that the functional effects of acute exercise are controlled by association of TTs (containing Orai1 proteins) with SR-stacks (containing STIM1 proteins) in the I band, with an increase of TT/SR contact length that provides a greater surface area for STIM1-Orai1 interaction. The role of SR-SR interfaces that lack a TT element remains unclear. However, SR-stacks containing multiple elements virtually identical to those formed in muscle after exercise, are also observed in non-muscle cells following STIM1 overexpression (Orci et al., 2009; Perni et al., 2015). Interestingly, both ER-ER contacts in non-muscle cells overexpressing STIM1 and SR-SR contacts in muscle after acute exercise exhibit small electron dense bridges within a similar junctional gap width (~8 nm). These similarities in membrane structure and gap width are consistent with the small electron dense bridges observed in EM images reflecting STIM1 proteins. Similar to the ‘diffusion trap’ model of STIM1-Orai1 coupling in non-excitable cells proposed previously (Wu et al., 2014), one possible interpretation of these findings is that STIM1-containing SR-stacks could be needed to efficiently trap Orai1 channels during TT elongation into the I band.

An unexpected finding of this study was the demonstration of significant Mn²⁺ quench in the absence of thapsigargin/cyclopiazonic acid-induced store depletion (constitutive Ca²⁺ entry) in FDB fibers isolated from mice < 1 hr after treadmill exercise (Figure 4). As the constitutive Ca²⁺ entry in these fibers was rapidly blocked by application of BTP-2 (Figure 4—figure supplement 1), the constitutive entry in these fibers is unlikely to represent increased susceptibility of fibers to damage shortly after exercise. In support of this idea, the constitutive Ca²⁺ entry observed <1 hr after exercise is absent in fibers from two separate mouse models deficient in Orai1 function (Figure 7 and Figure 7—figure supplement 1). These findings suggest that the constitutive Ca²⁺ entry is mediated by Orai1 channels (rather than TrpC or mechano-sensitive channels). D1ER measurements of ‘spatially-averaged’ free Ca²⁺ concentration in the SR were not significantly different after exercise (though areas of local depletion are possible). It is important to note, however, that D1ER localization studies indicate that the majority of the D1ER signal originated from the triad junction (Figure 5—figure supplement 2A). Thus, the D1ER measurements suggest that the free Ca²⁺ concentration within the triad junction is not different after exercise. Thus, constitutive Ca²⁺ entry observed after exercise most likely does not originate from Orai1 channels within the triad junction. Rather, constitutive entry may arise from Orai1 channels in another location, possibly CEUs assembled during exercise in the I band region of the sarcomere that are not well-reflected in the spatially-averaged D1ER signal. These observations support the possibility that CEUs represent the site of constitutive Ca²⁺ entry after exercise. An alternative explanation is that exercise could produce a signal that directly activates Orai1 independent of store depletion.

Assuming no changes in the properties of sarcolemmal Ca²⁺ efflux mechanisms, the increase in constitutive Ca²⁺ entry observed <1 hr after exercise could explain the elevation in resting Ca²⁺ concentration observed at this time point (Figure 5E and Figure 5—figure supplement 1). Again, partial Ca²⁺ depletion within SR-stacks of the CEU represents one possible mechanism for the constitutive entry observed immediately following exercise. Alternatively, as lower levels of store depletion are sufficient for Stim2 to activate Orai1-dependent Ca²⁺ entry (Brandman et al., 2007; Thiel et al., 2013), the constitutive Ca²⁺ entry observed after exercise could reflect Stim2-mediated activation of Orai1 channels within the CEUs. Thus, it will be important for future studies to more definitively assess SERCA and Stim2 expression within CEUs, determine the relative distribution of the short and long forms of STIM1 within CEUs (Michelucci et al., 2018), and quantitatively model Ca²⁺ binding and diffusion within and out of these structures.

Another observation that deserves consideration is the non-linear correspondence between exercise-induced changes in structure (TT/SR contact length increases five fold; Figure 2E) and SOCE function (~65% increase in maximal rate of Mn²⁺ quench; Figure 3B) in FDB muscle. One possibility is that, as proposed above, CEUs may reflect the subcellular location for the constitutive SOCE observed <1 hr after exercise. However, given that total releasable Ca²⁺ store content at rest was reduced <1 hr after exercise, it is possible that pre-existing STIM and Orai1 complexes distinct from newly formed CEUs could also contribute to the observed increase in SOCE function.

We investigated the mechanism by which increased SOCE following acute exercise increases peak Ca²⁺ transient amplitude during repetitive, high-frequency stimulation. Conceivably, increased total (Figure 3) and constitutive (Figure 4) SOCE activity <1 hr after exercise could potentiate peak Ca²⁺ transient amplitude either by increasing total releasable SR Ca²⁺ content or elevating myoplasmic Ca²⁺ levels enough to reduce fast buffering. Alternatively, SERCA activity could be inhibited after exercise due to glycogen depletion. Kinetic analysis of twitch Ca²⁺ transient decay before and after 10 stimulus trains in FDB fibers from control and exercised mice did not reveal a significant change in either myoplasmic Ca²⁺ buffering or SERCA-mediated SR Ca²⁺ reuptake (Figure 5—figure supplement 3). On the other hand, both total releasable Ca²⁺ store content (Figure 5D) and resting myoplasmic Ca²⁺ concentration (Figure 5E) were significantly increased after 10 stimulus trains in FDB fibers from mice < 1 hr after exercise. Together, these findings are consistent with the observed increase in peak Ca²⁺ transient amplitude (and force production) after acute exercise resulting, at least in part, from enhanced SOCE activity promoting SR refilling and total releasable Ca²⁺ content to a level sufficient to augment Ca²⁺ flux.

EDL muscles isolated from mice < 1 hr after treadmill exercise exhibit an increased ability to produce sustained force during repetitive stimulation (Figure 6) (Boncompagni et al., 2017). Muscle force production shows a rebound increment in peak-specific force (between stimulus trains 2–12), referred to as the bump-phase of the repetitive stimulation contraction curve. The following observations are consistent with this bump-phase reflecting the contribution of Orai1-dependent SOCE: 1) it is reduced by interventions (BTP-2, 2-APB, 0 Ca²⁺) that reduce SOCE (Boncompagni et al., 2017); 2) it is increased <1 hr after treadmill exercise when SOCE is also increased; 3) it is unaltered 6 and 24 hr after treadmill exercise when SOCE activity has returned to control levels; 4) it is absent in mice lacking Orai1-dependent Ca²⁺ entry both under control conditions and after acute exercise. As some mouse models have been shown to exhibit an increase in basal levels of CEUs similar to those observed immediately following exercise (Boncompagni et al., 2012a; Boncompagni et al., 2012b; Ko et al., 2011), it will be important for future studies to determine if muscles from these mice also exhibit an increase in both SOCE and the bump-phase of the repetitive stimulation contraction curve.

In conclusion, the findings reported here support the idea that CEUs formed after acute exercise represent an adaptive response of skeletal muscle to exercise that augments Orai1-dependent Ca²⁺ entry to optimize myoplasmic Ca²⁺ dynamics in a manner that limits muscle force decline during sustained activation.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Antonio Michelucci

   1. Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, United States
   2. Center for Research on Ageing and Translational Medicine (CeSI-MeT), University Gabriele d'Annunzio, Chieti, Italy

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0720-3009

2. Simona Boncompagni

   1. Center for Research on Ageing and Translational Medicine (CeSI-MeT), University Gabriele d'Annunzio, Chieti, Italy
   2. Department of Neuroscience, Imaging and Clinical Sciences (DNICS), University Gabriele d'Annunzio, Chieti, Italy

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5308-5069

3. Laura Pietrangelo

   1. Center for Research on Ageing and Translational Medicine (CeSI-MeT), University Gabriele d'Annunzio, Chieti, Italy
   2. Department of Neuroscience, Imaging and Clinical Sciences (DNICS), University Gabriele d'Annunzio, Chieti, Italy

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization

   Competing interests

   No competing interests declared

4. Maricela García-Castañeda

   Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

5. Takahiro Takano

   Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Methodology

   Competing interests

   No competing interests declared

6. Sundeep Malik

   Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Methodology

   Competing interests

   No competing interests declared

7. Robert T Dirksen

   Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Feliciano Protasi

   For correspondence

   robert_dirksen@urmc.rochester.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3182-1755

8. Feliciano Protasi

   1. Center for Research on Ageing and Translational Medicine (CeSI-MeT), University Gabriele d'Annunzio, Chieti, Italy
   2. Department of Medicine and Ageing Sciences (DMSI), University Gabriele d'Annunzio, Chieti, Italy

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Robert T Dirksen

   Competing interests

   No competing interests declared

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