Muscle-specific Ryanodine receptor 1 properties underlie limb-girdle muscular dystrophy 2B/R2 progression

Aldo Meizoso-Huesca, Cedric R. Lamboley, James R. Krycer, Mark P. Hodson, James E. Hudson and Bradley S. Launikonis ()
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Aldo Meizoso-Huesca: The University of Queensland
Cedric R. Lamboley: The University of Queensland
James R. Krycer: QIMR Berghofer Medical Research Institute
Mark P. Hodson: QIMR Berghofer Medical Research Institute
James E. Hudson: The University of Queensland
Bradley S. Launikonis: The University of Queensland

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58393-2

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