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Ryanodine receptor leak triggers fiber Ca2+ redistribution to preserve force and elevate basal metabolism in skeletal muscle

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posted on 2021-11-19, 00:22 authored by CR Lamboley, L Pearce, C Seng, A Meizoso-Huesca, DP Singh, Barnaby FrankishBarnaby Frankish, V Kaura, HP Lo, C Ferguson, PD Allen, PM Hopkins, RG Parton, Robyn MurphyRobyn Murphy, Christopher Van-Der-PoelChristopher Van-Der-Poel, CJ Barclay, BS Launikonis
Muscle contraction depends on tightly regulated Ca2+ release. Aberrant Ca2+ leak through ryanodine receptor 1 (RyR1) on the sarcoplasmic reticulum (SR) membrane can lead to heatstroke and malignant hyperthermia (MH) susceptibility, as well as severe myopathy. However, the mechanism by which Ca2+ leak drives these pathologies is unknown. Here, we investigate the effects of four mouse genotypes with increasingly severe RyR1 leak in skeletal muscle fibers. We find that RyR1 Ca2+ leak initiates a cascade of events that cause precise redistribution of Ca2+ among the SR, cytoplasm, and mitochondria through altering the Ca2+ permeability of the transverse tubular system membrane. This redistribution of Ca2+ allows mice with moderate RyR1 leak to maintain normal function; however, severe RyR1 leak with RYR1 mutations reduces the capacity to generate force. Our results reveal the mechanism underlying force preservation, increased ATP metabolism, and susceptibility to MH in individuals with gain-of-function RYR1 mutations.


This work was supported by an AFM-Telethon Research Grant (22181) and Australian Research Council (ARC) Discovery Projects (DP180100937 and DP200100435) to B.S.L., the National Health and Medical Research Council of Australia (grants APP1140064 and APP1150083 and fellowship APP1156489) to R.G.P., the NIH National Institute of Arthritis, Musculoskeletal, and Skin Diseases (R01AR068897) to P.D.A. and P.H.M., and the Medical Research Council grant MR/N002407/1 (London, UK) to V.K. R.G.P. was supported by the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology CE140100036. The authors acknowledge the use of the Microscopy Australia Research Facility at the Center for Microscopy and Microanalysis at The University of Queensland.


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Science Advances





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American Association for the Advancement of Science



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