Skeletal muscle contraction relies on both high-fidelity calcium (Ca²⁺) signals and robust capacity for adenosine triphosphate (ATP) generation. Ca²⁺ release units (CRUs) are highly organized junctions between the terminal cisternae of the sarcoplasmic reticulum (SR) and the transverse tubule (T-tubule). CRUs provide the structural framework for rapid elevations in myoplasmic Ca²⁺ during excitation–contraction (EC) coupling, the process whereby depolarization of the T-tubule membrane triggers SR Ca²⁺ release through ryanodine receptor-1 (RyR1) channels. Under conditions of local or global depletion of SR Ca²⁺ stores, store-operated Ca²⁺ entry (SOCE) provides an additional source of Ca²⁺ that originates from the extracellular space. In addition to Ca²⁺, skeletal muscle also requires ATP to both produce force and to replenish SR Ca²⁺ stores. Mitochondria are the principal intracellular organelles responsible for ATP production via aerobic respiration. This review provides a broad overview of the literature supporting a role for impaired Ca²⁺ handling, dysfunctional Ca²⁺-dependent production of reactive oxygen/nitrogen species (ROS/RNS), and structural/functional alterations in CRUs and mitochondria in the loss of muscle mass, reduction in muscle contractility, and increase in muscle damage in sarcopenia and a wide range of muscle disorders including muscular dystrophy, rhabdomyolysis, central core disease, and disuse atrophy. Understanding the impact of these processes on normal muscle function will provide important insights into potential therapeutic targets designed to prevent or reverse muscle dysfunction during aging and disease.

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.

Store-operated Ca²⁺ entry (SOCE) is a ubiquitous Ca²⁺ influx mechanism triggered by depletion of Ca²⁺ stores from the endoplasmic/sarcoplasmic reticulum (ER/SR). We recently reported that acute exercise in WT mice drives the formation of Ca²⁺ entry units (CEUs), intracellular junctions that contain STIM1 and Orai1, the two key proteins mediating SOCE. The presence of CEUs correlates with increased constitutive- and store-operated Ca²⁺ entry, as well as sustained Ca²⁺ release and force generation during repetitive stimulation. Skeletal muscle from mice lacking calsequestrin-1 (CASQ1-null), the primary Ca²⁺-binding protein in the lumen of SR terminal cisternae, exhibits significantly reduced total Ca²⁺ store content and marked SR Ca²⁺ depletion during high-frequency stimulation. Here, we report that CEUs are constitutively assembled in extensor digitorum longus (EDL) and flexor digitorum brevis (FDB) muscles of sedentary CASQ1-null mice. The higher density of CEUs in EDL (39.6 ± 2.1/100 µm² versus 2.0 ± 0.3/100 µm²) and FDB (16.7 ± 1.0/100 µm² versus 2.7 ± 0.5/100 µm²) muscles of CASQ1-null compared with WT mice correlated with enhanced constitutive- and store-operated Ca²⁺ entry and increased expression of STIM1, Orai1, and SERCA. The higher ability to recover Ca²⁺ ions via SOCE in CASQ1-null muscle served to promote enhanced maintenance of peak Ca²⁺ transient amplitude, increased dependence of luminal SR Ca²⁺ replenishment on BTP-2-sensitive SOCE, and increased maintenance of contractile force during repetitive, high-frequency stimulation. Together, these data suggest that muscles from CASQ1-null mice compensate for the lack of CASQ1 and reduction in total releasable SR Ca²⁺ content by assembling CEUs to promote constitutive and store-operated Ca²⁺ entry.

All animal cells control their volume through a complex set of mechanisms, both to counteract osmotic perturbations of the environment and to enable numerous vital biological processes, such as proliferation, apoptosis, and migration. The ability of cells to adjust their volume depends on the activity of ion channels and transporters which, by moving K⁺, Na⁺, and Cl⁻ ions across the plasma membrane, generate the osmotic gradient that drives water in and out of the cell. In 2010, Patapoutian’s group identified a small family of evolutionarily conserved, Ca²⁺-permeable mechanosensitive channels, Piezo1 and Piezo2, as essential components of the mechanically activated current that mediates mechanotransduction in vertebrates. Piezo1 is expressed in several tissues and its opening is promoted by a wide range of mechanical stimuli, including membrane stretch/deformation and osmotic stress. Piezo1-mediated Ca²⁺ influx is used by the cell to convert mechanical forces into cytosolic Ca²⁺ signals that control diverse cellular functions such as migration and cell death, both dependent on changes in cell volume and shape. The crucial role of Piezo1 in the regulation of cell volume was first demonstrated in erythrocytes, which need to reduce their volume to pass through narrow capillaries. In HEK293 cells, increased expression of Piezo1 was found to enhance the regulatory volume decrease (RVD), the process whereby the cell re-establishes its original volume after osmotic shock-induced swelling, and it does so through Ca²⁺-dependent modulation of the volume-regulated anion channels. More recently we reported that Piezo1 controls the RVD in glioblastoma cells via the modulation of Ca²⁺-activated K⁺ channels. To date, however, the mechanisms through which this mechanosensitive channel controls cell volume and maintains its homeostasis have been poorly investigated and are still far from being understood. The present review aims to provide a broad overview of the literature discussing the recent advances on this topic.

Glioblastoma (GBM), the most lethal form of brain tumors, bases its malignancy on the strong ability of its cells to migrate and invade the narrow spaces of healthy brain parenchyma. Cell migration and invasion are both critically dependent on changes in cell volume and shape driven by the transmembrane transport of osmotically important ions such as K⁺ and Cl⁻. However, while the Cl⁻ channels participating in cell volume regulation have been clearly identified, the precise nature of the K⁺ channels involved is still uncertain. Using a combination of electrophysiological and imaging approaches in GBM U87‐MG cells, we found that hypotonic‐induced cell swelling triggered the opening of Ca²⁺‐activated K⁺ (K_Ca) channels of large and intermediate conductance (BK_Ca and IK_Ca, respectively), both highly expressed in GBM cells. The influx of Ca²⁺ mediated by the hypotonic‐induced activation of mechanosensitive channels was found to be a key step for opening both the BK_Ca and the IK_Ca channels. Finally, the activation of both K_Ca channels mediated by mechanosensitive channels was found to be essential for the development of the regulatory volume decrease following hypotonic shock. Taken together, these data indicate that K_Ca channels are the main K⁺ channels responsible for the volume regulation in U87‐MG cells.