Molecular genetics of skeletal muscle diseases associated with abnormal excitation–contraction coupling

Abstract

Skeletal muscle excitation-contraction coupling (ECC) is a highly specialized process that converts membrane depolarization into contraction through tightly regulated intracellular Ca²⁺ dynamics. Recent advances in molecular genetics have expanded the spectrum of skeletal muscle disorders associated with ECC-related proteins, including congenital myopathies, malignant hyperthermia susceptibility, exertional rhabdomyolysis, exertional heat illness, and related episodic disorders. Although these disorders have traditionally been classified according to clinical manifestations, pathological findings, and causative genes, accumulating evidence suggests that genetically and clinically heterogeneous disorders converge on overlapping abnormalities in intracellular Ca²⁺ handling and ECC function. This review provides an integrative overview of ECC-related skeletal muscle disorders from the perspective of shared abnormalities in intracellular Ca²⁺ handling and the molecular mechanisms that underlie them. We discuss how pathogenic variants affecting the voltage-sensing skeletal muscle L-type calcium channel (CaV1.1), the ryanodine receptor type 1 (RyR1), and other triad-associated proteins disrupt Ca²⁺ release from the sarcoplasmic reticulum (SR), luminal Ca²⁺ regulation, and SR Ca²⁺ reuptake, leading to diverse but partially convergent phenotypes. We also discuss secondary pathological changes associated with chronic intracellular Ca²⁺ dysregulation, including mitochondrial dysfunction, oxidative stress, and skeletal muscle remodeling. Finally, we present a functional perspective centered on intracellular Ca²⁺ handling that complements conventional genetic and clinicopathological classifications of ECC-related skeletal muscle disorders.