2025
Nat Commun. 2025 Mar 28;16(1):3056. doi: 10.1038/s41467-025-58393-2.
Muscle-specific Ryanodine receptor 1 properties underlie limb-girdle muscular dystrophy 2B/R2 progression
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia. School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
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Abstract
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 channel of limb-girdle muscle. This alters 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 alters basal Ca2+ movements. Our results show that muscle-specific pathology in dysferlin-null mice is linked to increased ryanodine receptor 1 Ca2+ leak.
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