Junctional membrane Ca ²⁺ dynamics in human muscle fibers are altered by malignant hyperthermia causative RyR mutation

Significance In human muscle with ryanodine receptor (RyR) variants, there is expected to be a change in the basal RyRs Ca 2+ leak that may alter local Ca 2+ dynamics. It is not currently possible to assess these basal Ca 2+ dynamics in human muscle. By trapping a Ca 2+ -sensitive fluorescent dye in the transverse tubular (t)-system of freshly biopsied human skeletal muscle fibers we could detect tiny local RyR-dependent Ca 2+ movements. We show that malignant hyperthermia (MH) causative RyR variant human muscle displays a chronically different RyR Ca 2+ leak which reconfigures the Ca 2+ -handling properties by the t-system. This approach can be used to assess human muscle for function and pathogenicity of other RyR variants of uncertain significance, MH susceptibility, and assessment of drugs targeted to the Ca 2+ -handling proteins.