PR002361 (Project)

Description:Ryanodine receptor 1 Ca2+ leak is a signal in skeletal muscle, but chronic leak can underlie pathology. Here we show that in healthy male mouse, limb-girdle muscle presents higher sympathetic input, elevated ryanodine receptor 1 basal phosphorylation, Ca2+ leak and mitochondrial Ca2+ content compared to distal leg muscles. These regional differences are consistent with heat generation in resting muscle to maintain core temperature. The dysferlin-null mouse develops severe pathology in the limb-girdle but not leg muscles. Absence of dysferlin disrupts dihydropyridine receptors’ inhibitory control over ryanodine receptor 1 leak, synergistically increasing leak through the already phosphorylated receptor of limb-girdle muscle, altering Ca2+ handling and distribution leading to reactive oxygen species production prior to disease onset. With age, oxidation of Ca2+ -handling proteins in dysferlin-null limb-girdle muscle exacerbated basal Ca2+ movements. Our results show that muscle-specific pathology in dysferlin-null mice is triggered by increased ryanodine receptor 1 Ca2+ leak.