Transverse tubule remodeling enhances Orai1-dependent Ca²⁺ entry in skeletal muscle

Exercise promotes the formation of intracellular junctions in skeletal muscle between stacks of sarcoplasmic reticulum (SR) cisternae and extensions of transverse-tubules (TT) that increase co-localization of proteins required for store-operated Ca²⁺ entry (SOCE). Here, we report that SOCE, peak Ca²⁺ transient amplitude and muscle force production during repetitive stimulation are increased after exercise in parallel with the time course of TT association with SR-stacks. Unexpectedly, exercise also activated constitutive Ca²⁺ entry coincident with a modest decrease in total releasable Ca²⁺ store content. Importantly, this decrease in releasable Ca²⁺ store content observed after exercise was reversed by repetitive high-frequency stimulation, consistent with enhanced SOCE. The functional benefits of exercise on SOCE, constitutive Ca²⁺ entry and muscle force production were lost in mice with muscle-specific loss of Orai1 function. These results indicate that TT association with SR-stacks enhances Orai1-dependent SOCE to optimize Ca²⁺ dynamics and muscle contractile function during acute exercise.