IntroductionSkeletal muscle plays an essential role in voluntary movement, posture maintenance, respiration, and metabolic homeostasis. To support these diverse physiological functions, the fibers of the skeletal muscle must repeatedly generate rapid and coordinated contractions in response to neuronal stimulation. This process depends on excitation–contraction coupling (ECC) [1], a highly specialized mechanism that converts membrane depolarization into mechanical force generation through tightly regulated intracellular Ca²⁺ dynamics.ECC in skeletal muscle is mediated by coordinated interactions between the voltage-sensing α1S subunit of the skeletal muscle L-type calcium channel (CaV1.1), the ryanodine receptor type 1 (RyR1), and multiple structurally and functionally interconnected proteins located within the triad [2, 3]. Membrane depolarization propagating through the transverse tubule (T-tubule) system activates CaV1.1, which mechanically couples to RyR1 and induces rapid release of Ca²⁺ from the sarcoplasmic reticulum (SR) required for skeletal muscle contraction. Subsequent Ca²⁺ reuptake into the SR by sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) restores the resting conditions and enables repetitive contractile activity. Because skeletal muscle contraction depends on the precise spatial and temporal regulation of SR Ca²⁺ release and recovery, abnormalities affecting the ECC machinery can alter skeletal muscle function.Persistent disturbances in intracellular Ca²⁺ homeostasis are associated with impaired force generation, energetic stress, altered intracellular signaling pathways, and progressive remodeling of skeletal muscle function [4,5,6,7]. Consequently, abnormalities associated with ECC are increasingly recognized as important contributors to diverse skeletal muscle diseases [8]. Historically, skeletal muscle disorders have been classified according to clinical manifestations, pathological findings, and causative genes, and this framework remains fundamental in clinical neuromuscular medicine. However, recent advances in molecular genetics and next-generation sequencing have substantially expanded the spectrum of disorders associated with ECC-related proteins and have further revealed considerable overlap among traditionally distinct disease categories [9].Pathogenic variants have been identified in genes involved in SR Ca²⁺ release, voltage sensing, triad organization, luminal Ca²⁺ regulation, and SR Ca²⁺ reuptake [4, 9]. These disorders include congenital myopathies, malignant hyperthermia susceptibility (MHS), exertional rhabdomyolysis, exertional heat illness, and related conditions [10]. Increasing evidence suggests that clinically and genetically distinct skeletal muscle disorders can converge with partially overlapping abnormalities in intracellular Ca²⁺ handling [4]. Meanwhile, variants within a single ECC-associated gene can produce remarkably heterogeneous and overlapping clinical, pathological, and physiological phenotypes [9]. These observations have increasingly highlighted the importance of interpreting skeletal muscle diseases not only according to clinical or genetic classifications, but also through the functional framework of abnormalities associated with ECC.This complexity is particularly evident in RYR1-related disorders, which represent a broad spectrum of diseases that include congenital myopathies, episodic hypermetabolic disorders, and mixed phenotypes [8]. Depending on the specific variant and physiological context, RyR1 abnormalities can result in excessive SR Ca²⁺ leak, abnormal sensitivity to trigger stimuli, impaired depolarization-induced Ca²⁺ release, ECC uncoupling, or luminal Ca²⁺ dysregulation. Moreover, chronic Ca²⁺ dysregulation is associated with secondarily induced mitochondrial dysfunction [5], oxidative stress [11, 12], altered cellular signaling [13], and progressive structural remodeling [13], which further influences disease progression and phenotypic diversity over time. These observations support the concept that functional abnormalities involving ECC-associated molecular systems can serve as a complementary framework to understand genetically and clinically heterogeneous skeletal muscle diseases.Building on this concept, the present review aims to integrate genetically heterogeneous ECC-related skeletal muscle diseases from the perspective of shared abnormalities in ECC-associated intracellular Ca²⁺ regulation, rather than discussing them primarily according to individual genes or clinicopathological categories. To maintain the focus, disorders primarily involving store-operated Ca²⁺ entry (SOCE), membrane remodeling, or skeletal muscle channelopathies such as periodic paralysis are not discussed further.Molecular basis of ECC in skeletal muscleTriadic organization and depolarization-induced SR Ca²+ releaseECC in skeletal muscle is initiated by membrane depolarization generated by muscle action potentials at the neuromuscular junction (NMJ) and propagated through the T-tubule membrane [3]. CaV1.1 functions as a voltage sensor responsible for detecting membrane depolarization and mechanically activating RyR1 located in the terminal cisternae of the SR. This highly specialized arrangement enables rapid depolarization-induced Ca2+ release (DICR) through RyR1 required for synchronized skeletal muscle contraction [14,15,16,17]. Because skeletal muscle fibers are large and highly organized cells, electrical signals generated in the NMJ must be efficiently transmitted to intracellular membrane structures. The T-tubule system enables the rapid propagation of depolarization into the interior of muscle fibers, thereby facilitating coordinated SR Ca²⁺ release throughout the fiber [15]. This coupling between membrane excitation and SR Ca²⁺ release represents the central mechanism underlying skeletal muscle contraction. Efficient and synchronized activation of this process is essential to maintain normal skeletal muscle performance (Fig. 1).Fig. 1Full size imageMolecular basis of excitation–contraction coupling in skeletal muscle (ECC). Major molecular components and sequential processes involved in skeletal muscle ECC. ① Neuromuscular transmission; ② propagation of depolarization; ③ voltage sensing; ④ SR Ca²⁺ release; ⑤ SR Ca²⁺ reuptake; and ⑥ luminal regulation. Abbreviations: NMJ, neuromuscular junction; SR, sarcoplasmic reticulum; CaV1.1, skeletal muscle L-type calcium channel α1S subunit; β1a, voltage-gated calcium channel β1a subunit; STAC3, SH3 and cysteine-rich domain-containing protein 3; RyR1, ryanodine receptor type 1; CASQ, calsequestrin; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPaseTriads are specialized membrane junctions in which T-tubules are tightly apposed to the terminal cisternae of the SR [14]. These highly organized structures enable efficient coupling between membrane depolarization and SR Ca²⁺ release in mature skeletal muscle fibers [14, 15]. Precise alignment between the T-tubule and SR membranes is essential for the rapid and synchronized activation of RyR1 channels throughout the muscle fiber. Structural disruption of the triads alters RyR1 activation and reduces the fidelity of ECC in skeletal muscle fibers. The characteristic positioning of the triads adjacent to the contractile apparatus facilitates rapid and uniform DICR throughout the muscle fiber, thereby ensuring coordinated skeletal muscle contraction.RyR1 forms one of the largest ion channels in mammalian cells and functions as the main SR Ca²⁺ release channel in skeletal muscle [14]. Because RyR1-mediated Ca²⁺ release directly regulates the activation of the contractile apparatus [18], stabilization of RyR1 channel gating is essential for normal skeletal muscle physiology [14, 16]. Under physiological conditions, the RyR1 channels remain closed at rest and open transiently during depolarization-induced activation. Therefore, tight regulation of RyR1 channel gating is required to maintain appropriate Ca²⁺ release during ECC. Dysregulated RyR1 activation, including both excessive and insufficient channel activity, disrupts skeletal muscle physiology through distinct pathophysiological mechanisms [16, 19].Persistent abnormalities in intracellular Ca²⁺ regulation can affect both acute contractile activity and long-term skeletal muscle homeostasis [19,20,21]. Elevated cytosolic Ca²⁺ levels promote cellular stress and structural instability, while insufficient DICR impairs activation of the contractile apparatus and compromises repetitive muscle performance [4, 20]. In addition to its role in ECC-associated Ca²⁺ release, intracellular Ca²⁺ also functions as a signaling mediator involved in skeletal muscle adaptation and maintenance. Consequently, disruption of RyR1-mediated Ca²⁺ release and associated Ca²⁺ homeostasis can exert broader physiological effects beyond impaired contractile function [21]. Together, these observations emphasize the importance of balanced and tightly regulated intracellular Ca²⁺ handling in skeletal muscle.Triad-associated proteins and SR luminal regulatorsIn addition to CaV1.1 and RyR1, several triad-associated proteins that participate in or support the ECC machinery are required for stable Ca²⁺ handling in skeletal muscle [15]. Among these, SH3 and cysteine-rich domain 3 (STAC3) functions as an important auxiliary component of the ECC machinery that supports normal functional coupling between CaV1.1 and RyR1 [22,23,24], while junctophilins stabilize membrane contact sites between T-tubules and SR and help preserve the structural organization of triads [25]. Disruption of these systems impairs depolarization-induced SR Ca²⁺ release and ultimately compromises skeletal muscle contractility. Together, these proteins support the assembly and maintenance of the triadic complex, providing the highly organized membrane architecture required for efficient communication between membrane depolarization and intracellular Ca²⁺ release. Thus, stable Ca²⁺ handling in skeletal muscle depends not only on CaV1.1 and RyR1 themselves, but also on the integrity of their associated triad-localized regulatory and scaffolding systems.Whereas the preceding regulatory systems primarily support the membrane-associated DICR machinery, the luminal side of the SR contributes to the Ca²⁺ handling of skeletal muscle by modulating RyR1 gating [26]. Within the SR lumen, calsequestrin (CASQ1) [27], triadin (TRDN) [28], and junctin (encoded by the ASPH gene through alternative splicing) [29] form a functionally interconnected regulatory system that controls SR Ca²⁺ storage and RyR1-mediated Ca²⁺ release. CASQ1 serves as the major intraluminal Ca²⁺ buffering protein in skeletal muscle and supports the large Ca²⁺ storage capacity of the SR required for repetitive contraction. By assembling into a multi-protein complex with TRDN, junctin, and RyR1, CASQ1 also enables changes in luminal Ca²⁺ load to influence RyR1 gating. TRDN and junctin contribute to luminal communication between CASQ1 and RyR1 and participate in the regulation of SR Ca²⁺ release in response to changes in intraluminal Ca²⁺ conditions. Through these coordinated interactions, the luminal regulatory system helps maintain stable availability of SR Ca²⁺ during repeated cycles of contraction and relaxation. Because skeletal muscle fibers repeatedly mobilize large amounts of intracellular Ca²⁺ within short time intervals, disruption of luminal Ca²⁺ regulatory systems can affect repetitive Ca²⁺ release and compromise sustained muscle performance. Thus, stable skeletal muscle ECC depends not only on membrane-associated DICR machinery but also on tightly regulated intraluminal SR Ca²⁺ homeostasis.Recovery of SR Ca²+ and restoration of resting stateTermination of skeletal muscle contraction requires efficient restoration of cytosolic and SR Ca²⁺ balance following SR Ca²⁺ release [18, 30]. The SR Ca²⁺-ATPase (SERCA) pumps Ca²⁺ from the cytosol back into the SR, thereby lowering cytosolic Ca²⁺, promoting Ca²⁺ dissociation from troponin C, and driving the return of skeletal muscle fibers to the relaxed state [31,32,33]. At the same time, SERCA-mediated Ca²⁺ reuptake replenishes SR Ca²⁺ stores and thus prepares the fiber for subsequent cycles of DICR and contraction. Efficient SERCA function is therefore essential for normal skeletal muscle ECC and intracellular Ca²⁺ homeostasis.Efficient SR Ca²⁺ recovery is particularly important during repetitive muscle activity [21], when skeletal muscle fibers must mobilize and restore large amounts of intracellular Ca²⁺ within short time intervals. In this context, ATP-dependent Ca²⁺ reuptake helps to prevent prolonged elevation of cytosolic Ca²⁺, limit metabolic stress, and maintain the efficiency of repetitive contraction–relaxation cycling. Because SERCA activity relies on continuous consumption of ATP, disturbances in cellular energy balance can secondarily impair intracellular Ca²⁺ recovery and thus reduce skeletal muscle performance.Impaired SR Ca²⁺ reuptake contributes to exercise intolerance, delayed muscle relaxation, and chronic skeletal muscle dysfunction. These abnormalities become particularly evident during repetitive contractions, when rapid restoration of resting cytosolic Ca²⁺ concentrations and SR Ca²⁺ load is required [21, 34]. Persistent elevation of cytosolic Ca²⁺ can increase cellular stress and disrupt normal contractile function, while inadequate replenishment of SR Ca²⁺ stores compromises subsequent DICR. These considerations highlight the importance of coordinated, energy-dependent SR Ca²⁺ recovery systems in preserving normal skeletal muscle physiology.Functional classification of ECC abnormalitiesSkeletal muscle disorders associated with ECC dysfunction can be interpreted not only according to their genetic or histopathological classifications, but also according to the predominant abnormalities in intracellular Ca²⁺ handling that underlie their pathophysiology. Although ECC-related disorders exhibit marked genetic and clinical heterogeneity, many converge on partially overlapping defects in SR Ca²⁺ release, luminal regulation, or Ca²⁺ reuptake. From this functional perspective, these disorders can be categorized according to the main mechanisms by which Ca²⁺ homeostasis is disrupted. This framework facilitates mechanistic interpretation by integrating molecular genetics with alterations in intracellular Ca²⁺ handling. Importantly, these functional categories are not intended to replace traditional disease classification systems but rather provide a complementary perspective linking molecular defects with skeletal muscle dysfunction.In the following sections, functional abnormalities are discussed according to four major categories: excessive SR Ca²⁺ release and leak, impaired DICR and ECC uncoupling, abnormal luminal SR Ca²⁺ regulation, and reduced SR Ca²⁺ storage capacity, and defective SR Ca²⁺ reuptake (Fig. 2).Fig. 2Full size imageECC/SR Ca²⁺ handling abnormalities and their downstream consequences. Different abnormalities in excitation–contraction coupling (ECC) and sarcoplasmic reticulum Ca²⁺ handling alter intracellular Ca²⁺ homeostasis, resulting in overlapping functional phenotypes and diverse clinical outcomes. Dashed arrows indicate potential interactions. The proposed functional categories are not mutually exclusive, and multiple mechanisms may coexist within individual disorders. DICR depolarization-induced Ca²⁺ release, ECC excitation–contraction coupling, MH malignant hyperthermia, EHS exertional heat stroke, HypoPP hypokalemic periodic paralysis, SR sarcoplasmic reticulum, ER endoplasmic reticulumExcessive SR Ca²+ release and leakExcessive SR Ca²⁺ release represents one of the best-characterized functional abnormalities associated with ECC-related disorders [16, 35]. Gain-of-function variants in RYR1 or CACNA1S, the gene encoding CaV1.1 predispose skeletal muscle fibers to excessive SR Ca²⁺ release during exposure to triggering conditions such as volatile anesthetics, heat stress, or strenuous exercise [36]. Subsequently, sustained intracellular Ca²⁺ elevation promotes muscle contracture, rigidity, hypermetabolic state, and rhabdomyolysis, which constitute the main pathophysiological features of malignant hyperthermia (MH) episodes. In individuals with malignant hyperthermia susceptibility (MHS), these abnormalities remain clinically silent under basal conditions but become apparent following exposure to triggering anesthetic agents. Similar mechanisms involving dysregulated SR Ca²⁺ release have also been implicated in exertional heat stroke (EHS), exertional rhabdomyolysis, and related skeletal muscle disorders, in which symptoms are typically triggered by strenuous exercise and/or environmental heat stress.Increased local cytosolic Ca²⁺ can further amplify RyR1-mediated Ca²⁺ release through Ca²⁺-induced Ca²⁺ release (CICR) [37, 38], thus generating self-reinforcing elevation of intracellular Ca²⁺. Sustained activation of the contractile apparatus subsequently promotes prolonged muscle contraction and contracture, while excessive intracellular Ca²⁺ loading markedly increases ATP consumption and heat production. These metabolic changes are accompanied by increased oxygen demand, mitochondrial stress, and activation of downstream catabolic pathways, which ultimately contribute to myofiber injury and acute hypermetabolic states [36]. Under severe conditions, this self-amplifying cycle of abnormal Ca²⁺ release and metabolic stress can rapidly escalate into life-threatening hypermetabolic crises.Persistent abnormalities in SR Ca²⁺ release, including chronic SR Ca²⁺ leak, can disturb intracellular Ca²⁺ homeostasis and alter Ca²⁺-dependent signaling pathways in skeletal muscle fibers [39,40,41]. In addition to acute hypermetabolic reactions, sustained intracellular Ca²⁺ dysregulation is believed to progressively impair the cellular systems required for the maintenance and adaptation of skeletal muscle [42, 43]. Chronic elevation of cytosolic Ca²⁺ has been associated with Ca²⁺ stress and ER/SR stress, leading to mitochondrial dysfunction, oxidative and nitrosative stress [44], activation of Ca²⁺ -dependent proteolytic pathways, and disruption of myofibrillar architecture [42, 45]. Over time, these abnormalities can promote structural remodeling, degeneration of skeletal muscle fibers, and progressive myopathic changes [40, 43].Impaired depolarization-induced Ca2+ release and ECC uncouplingUnlike conditions with excessive SR Ca²⁺ release, many ECC-related disorders are characterized by insufficient depolarization-induced Ca²⁺ mobilization during muscle activation. In these disorders, impaired conversion of membrane depolarization into coordinated SR Ca²⁺ release limits activation of the contractile apparatus, so that skeletal muscle fibers cannot generate adequate force even when they are normally excited [46, 47]. As a result, patients present with chronic muscle weakness, easy fatigability, and myopathic changes on muscle biopsy, reflecting the functional consequences of defective DICR [46, 48].Loss-of-function alterations in RYR1 and/or reduced expression of RyR1 decrease DICR by reducing channel activity, destabilizing ECC, or lowering the amount of functional RyR1 available in the triad [46, 49]. Similarly, abnormalities involving CACNA1S, STAC3, or other triad-associated proteins impair voltage sensing or mechanical coupling between CaV1.1 and RyR1, thereby reducing DICR efficiency [50]. Because skeletal muscle contraction depends on efficient and precisely regulated Ca²⁺ mobilization, these defects in ECC lead to inefficient force production and increased susceptibility to fatigue, which over time contributes to chronic muscle weakness, muscle degeneration, and progressive myopathic changes [46, 48].In addition, abnormalities involving ECC-associated proteins can disrupt triad organization and reduce the efficiency or synchrony of DICR. In several congenital myopathies, altered triadic architecture is accompanied by chronic structural remodeling of skeletal muscle fibers, including disorganization of myofibrillar structures and progressive degenerative changes [47, 49]. At the histopathological level, these alterations can manifest as type 1 fiber predominance [51], fiber size variability, internal nuclei, and characteristic structural lesions such as central cores [52], multi-minicores [53], or centrally located nuclei [54], depending on the underlying genetic defect [46, 47]. Together, these findings support a close link between impaired ECC function, loss of triadic integrity, and long-term degeneration of skeletal muscle.Abnormal SR luminal Ca²+ regulation and reduced SR Ca²+ storage capacityThe SR lumen is not just a passive Ca²⁺ reservoir but a dynamic regulatory environment that stabilizes RyR1 activity and supports SR Ca²⁺ storage capacity [55, 56]. In skeletal muscle, abnormal luminal Ca²⁺ regulation can affect the ability of the SR to retain and rapidly supply Ca²⁺ during repeated cycles of contraction and relaxation, thereby reducing the availability of Ca²⁺ for DICR. As a result, defects in luminal control of SR Ca²⁺ homeostasis can compromise muscle performance, particularly under conditions of sustained activity or physiological stress [57].Alterations in CASQ1, TRDN, or junctin can reduce intraluminal Ca²⁺ buffering, disrupt luminal Ca²⁺ sensing, and destabilize SR Ca²⁺ release during repetitive stimulation [56, 57]. In affected skeletal muscle, reduced SR Ca²⁺ storage capacity leads to blunted Ca²⁺ transients, impaired activation of the contractile apparatus, and exercise-induced weakness or early fatigability. In contrast, some defects in luminal regulation destabilize RyR1-mediated Ca²⁺ release and promote abnormal Ca²⁺ leak, leading to myoplasmic Ca²⁺ overload and increased susceptibility to acute hypermetabolic or exercise-induced crises [58, 59]. Thus, depending on the underlying molecular defect, impaired luminal regulation can manifest either as insufficient Ca²⁺ availability for contraction or as destabilized Ca²⁺ handling with episodic decompensation.Clinically and pathologically, abnormalities in luminal regulatory proteins have been associated with chronic muscle weakness, exertional myalgia, episodic muscle stiffness, and susceptibility to stress-induced episodes [55, 60]. Muscle biopsies from affected individuals may show vacuolization, accumulation or mislocalization of SR components, variability in fiber size, and myofibrillar disorganization, often accompanied by alterations in the SR and triad architecture and abnormal SR cisternae at the ultrastructural level [55]. Experimental studies further indicate that disruption of luminal regulatory proteins impairs SR Ca²⁺ storage and destabilizes intracellular Ca²⁺ homeostasis during repeated contraction cycles, leading over time to structural remodeling and progressive myopathic changes [61]. Collectively, these observations support the view that impaired luminal Ca²⁺ regulation represents a distinct pathogenic mechanism within the broader spectrum of SR Ca²⁺ handling defects in skeletal muscle.Defective SR Ca²+ reuptakeDefective SR Ca²⁺ reuptake can alter both muscle relaxation and the maintenance of adequate SR Ca²⁺ stores required for subsequent Ca²⁺ release [62]. In skeletal muscle, impaired SR Ca²⁺ uptake can therefore contribute to two major forms of ECC dysfunction: prolonged cytosolic Ca²⁺elevation associated with delayed relaxation and insufficient restoration of releasable SR Ca²⁺ stores that secondarily alter DICR. These abnormalities can become particularly evident during repetitive muscle activity, when skeletal muscle fibers must repeatedly restore the intracellular Ca²⁺ balance in short time intervals.ATP2A1 variants that cause Brody myopathy provide a clinically recognizable example of impaired SR Ca²⁺reuptake [63]. ATP2A1 encodes SERCA1, the predominant SERCA isoform in fast-twitch skeletal muscle fibers. Patients typically present with exercise-induced muscle stiffness, impaired muscle relaxation, or intolerance to repetitive activity. Symptoms are often exacerbated during rapid or repeated movements, consistent with the physiological importance of rapid SR Ca²⁺ recovery during repetitive contraction-relaxation cycles. In many patients, fixed muscle weakness is absent or relatively mild, whereas delayed relaxation represents the predominant clinical manifestation.In addition to primary disorders related to ATP2A1, secondary impairment of SERCA activity may occur in conditions associated with chronic SR Ca²⁺ leak, oxidative stress, and mitochondrial dysfunction [42, 64, 65]. Chronic SR Ca²⁺ leak increases the workload of ATP-dependent Ca²⁺ reuptake systems, while mitochondrial dysfunction may further exacerbate defects in SR Ca²⁺ reuptake due to the close dependence of SERCA function on cellular energy metabolism. Although primary molecular defects differ considerably among these disorders, impaired restoration of cytosolic and SR Ca²⁺ balance appears to be a shared downstream functional abnormality, suggesting that defective recovery of SR Ca²⁺ is a common contributor to skeletal muscle dysfunction across genetically diverse conditions.ECC dysfunction across genetically diverse skeletal muscle diseasesThe preceding sections have discussed ECC abnormalities from a functional perspective, focusing on disturbances in SR Ca²⁺ release, luminal regulation, and Ca²⁺ recovery. In clinical practice, however, skeletal muscle diseases associated with ECC dysfunction are traditionally classified according to clinical manifestations, pathological findings, and causative genes. Increasing evidence from molecular genetics has demonstrated that these clinicopathological classifications frequently overlap, and that similar clinical phenotypes may arise from distinct abnormalities in intracellular Ca²⁺ handling [8, 9, 13, 20, 66,67,68]. Conversely, pathogenic variants in different genes can converge on shared defects in Ca²⁺ regulation and ECC. Table 1 summarizes these relationships by aligning causative genes with their predominant Ca²⁺-handling abnormalities and associated clinical phenotypes.Table 1 Representative Ca²⁺-handling abnormalities and associated clinical phenotypes in ECC-related skeletal muscle disordersFull size tableAmong the disorders associated with ECC, RYR1-related disorders constitute one of the broadest and most heterogeneous disease groups [10, 13, 20]. Clinical manifestations range from congenital hypotonia and delayed motor development to exertional myalgia, rhabdomyolysis, exertional heat illness, heat intolerance, and MHS, highlighting the continuum between congenital and stress-induced phenotypes. Histopathological findings are similarly heterogeneous and frequently overlap, including central cores [52], multi-minicores [53], centronuclear abnormalities [54], congenital fiber-type disproportion [51], dusty cores [69], and other nonspecific myopathic changes. These observations support the concept of an “RYR1-related disease spectrum”, in which congenital myopathies, episodic hypermetabolic disorders, and intermediate phenotypes are viewed as part of a continuous clinical spectrum rather than entirely distinct disease entities [9]. This spectrum likely reflects the heterogeneous effects of RYR1 variants on intracellular Ca²⁺ handling and ECC function.Importantly, the remarkable heterogeneity of RYR1-related disorders cannot be attributed to a single Ca²⁺-handling abnormality. Different RYR1 variants can produce diverse and partially overlapping disturbances in intracellular Ca²⁺ regulation, including excessive SR Ca²⁺ leak, impaired DICR, abnormal sensitivity to triggering stimuli, luminal Ca²⁺ dysregulation, ECC uncoupling, and secondary defects in SR Ca²⁺ recovery. Moreover, the functional consequences of RYR1 variants are not determined solely by altered channel activity. Variants may also influence RyR1 expression levels, channel stability, protein interactions within ECC-associated molecular complexes, and functional coupling with regulatory proteins. In addition, genetic modifiers and environmental factors may further contribute to the broad phenotypic variability observed among individuals with RYR1-related disorders [70, 71]. Disease manifestations may also evolve over time as secondary pathological changes accumulate, adding another layer of complexity to the disease spectrum.The same conceptual framework can also be extended to other genes associated with ECC. Variants involving CACNA1S [72], STAC3 [22], JPH1 [73], CASQ1 [74], TRDN [75], ASPH [76], and ATP2A1 [34] affect distinct components of the ECC machinery, including voltage sensing, triadic coupling, luminal Ca²⁺ regulation, and SR Ca²⁺ recovery [29, 77, 78]. Nevertheless, the resulting functional abnormalities frequently converge on overlapping disturbances in intracellular Ca²⁺ handling. Moreover, clinically similar phenotypes may arise from distinct molecular defects affecting different components of the ECC machinery. Together, these observations support the view that a functional framework centered on intracellular Ca²⁺ dysregulation provides a useful complement to traditional genetic and clinicopathological classifications for understanding skeletal muscle diseases associated with ECC.ConclusionsRecent advances in molecular genetics have considerably expanded the spectrum of skeletal muscle disorders associated with abnormalities in the molecular machinery underlying ECC. Pathogenic variants have been identified not only in RYR1, but also in genes involved in voltage sensing, triad organization, SR Ca²⁺ regulation, and Ca²⁺ recovery, highlighting the complexity of the molecular systems required to maintain normal skeletal muscle function. Increasing evidence suggests that genetically and clinically diverse skeletal muscle disorders often converge on shared disturbances in intracellular Ca²⁺ homeostasis despite affecting different components of the ECC machinery. From this functional perspective, ECC-related abnormalities can be broadly categorized into excessive SR Ca²⁺ leak and Ca²⁺ release, impaired DICR and ECC uncoupling, abnormal luminal Ca²⁺ regulation with reduced SR Ca²⁺ storage capacity, and defective SR Ca²⁺ reuptake.Importantly, this framework is not intended to replace established disease classification systems based on clinical manifestations, pathology, or causative genes. Rather, viewing skeletal muscle disorders through the lens of ECC-related functional abnormalities provides a complementary perspective that links molecular genetics findings with disturbances in intracellular Ca²⁺ handling. Further integration of molecular geneticswith functional analyses of ECC-associated molecular systems will advance our understanding of disease mechanisms across genetically heterogeneous skeletal muscle disorders and may facilitate the development of mechanism-based diagnostic and therapeutic strategies targeting Ca²⁺ handling.ReferencesSchneider MF, Chandler WK. Voltage dependent charge movement of skeletal muscle: a possible step in excitation-contraction coupling. Nature. 1973;242:244–6.Article CAS PubMed Google Scholar Rios E, Brum G. Involvement of dihydropyridine receptors in excitation-contraction coupling in skeletal muscle. Nature. 1987;325:717–20.Article CAS PubMed Google Scholar Dulhunty AF. Excitation-contraction coupling from the 1950s into the new millennium. Clin Exp Pharm Physiol. 2006;33:763–72.CAS Google Scholar Schartner V, Laporte J, Böhm J. Abnormal excitation-contraction coupling and calcium homeostasis in myopathies and cardiomyopathies. 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J Physiol. 2009;587:3095–100.CAS PubMed PubMed Central Google Scholar Download referencesAcknowledgementsThis work was partially supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant 23K19935 and 24K14407 to YE).Author informationAuthors and AffiliationsInstitute of Health and Sports Science & Medicine, Juntendo University, Tokyo, JapanYukari EndoDepartment of Pharmacology, Faculty of Medicine, Juntendo University, Tokyo, JapanYukari EndoAuthorsYukari EndoView author publicationsSearch author on:PubMed Google ScholarCorresponding authorCorrespondence to Yukari Endo.Ethics declarationsCompeting interestsThe author declares no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Rights and permissionsThis article is published under an open access license. 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