Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum

► We provide an overview of the major advances in our understanding of the etiology of MH, CCD and CPVT. ► MH and CPVT are caused by mutations in the ryanodine receptor (RyR) or calsequestrin. ► We propose that store overload-induced Ca2+ release is the common causal factor in MH and CPVT. ► We propose that there is non-uniformity of Ca2+ release from heterogeneous Ca2+ release units. ► This causes non-uniformity of muscle contraction, leading to structural muscle damage for CCD.