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

RyR1 Ca 2+ leak causes a cascade of events that shifts Ca 2+ to the cytoplasm and mitochondria, supporting force generation. Muscle contraction depends on tightly regulated Ca 2+ release. Aberrant Ca 2+ leak through ryanodine receptor 1 (RyR1) on the sarcoplasmic reticulum (SR) membrane can lead to...

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Bibliographic Details
Published in:Science advances 2021-10, Vol.7 (44), p.eabi7166-eabi7166
Main Authors: Lamboley, Cedric R, Pearce, Luke, Seng, Crystal, Meizoso-Huesca, Aldo, Singh, Daniel P, Frankish, Barnaby P, Kaura, Vikas, Lo, Harriet P, Ferguson, Charles, Allen, Paul D, Hopkins, Philip M, Parton, Robert G, Murphy, Robyn M, van der Poel, Chris, Barclay, Christopher J, Launikonis, Bradley S
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Language:English
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Summary:RyR1 Ca 2+ leak causes a cascade of events that shifts Ca 2+ to the cytoplasm and mitochondria, supporting force generation. Muscle contraction depends on tightly regulated Ca 2+ release. Aberrant Ca 2+ 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 Ca 2+ 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 Ca 2+ leak initiates a cascade of events that cause precise redistribution of Ca 2+ among the SR, cytoplasm, and mitochondria through altering the Ca 2+ permeability of the transverse tubular system membrane. This redistribution of Ca 2+ 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.
ISSN:2375-2548
DOI:10.1126/sciadv.abi7166