Ca 2+ leak through ryanodine receptor 1 regulates thermogenesis in resting skeletal muscle

Mammals rely on nonshivering thermogenesis (NST) from skeletal muscle so that cold temperatures can be tolerated. NST results from activity of the sarcoplasmic reticulum (SR) Ca pump in skeletal muscle, but the mechanisms that regulate this activity are unknown. Here, we develop a single-fiber assay...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2022-01, Vol.119 (4)
Main Authors: Meizoso-Huesca, Aldo, Pearce, Luke, Barclay, Christopher J, Launikonis, Bradley S
Format: Article
Language:English
Subjects:
Animals
Calcium - metabolism
Mice
Models, Biological
Muscle Fibers, Skeletal - metabolism
Muscle, Skeletal - metabolism
Rest
Ryanodine Receptor Calcium Release Channel - genetics
Ryanodine Receptor Calcium Release Channel - metabolism
Thermogenesis - genetics
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Summary:Mammals rely on nonshivering thermogenesis (NST) from skeletal muscle so that cold temperatures can be tolerated. NST results from activity of the sarcoplasmic reticulum (SR) Ca pump in skeletal muscle, but the mechanisms that regulate this activity are unknown. Here, we develop a single-fiber assay to investigate the role of Ca leak through ryanodine receptor 1 (RyR1) to generate heat at the SR Ca pump in resting muscle. By inhibiting a subpopulation of RyR1s in a single-fiber preparation via targeted delivery of ryanodine through transverse tubules, we achieve in-preparation isolation of RyR1 Ca leak. This maneuver provided a critical increase in signal-to-noise of the SR-temperature-sensitive dye ER thermoyellow fluorescence signal from the fiber to allow detection of SR temperature changes as either RyR1 or SR Ca pump activity was altered. We found that RyR1 Ca leak raises cytosolic [Ca ] in the local vicinity of the SR Ca pump to amplify thermogenesis. Furthermore, gene-dose-dependent increases in RyR1 leak in mutant mice result in progressive rises in leak-dependent heat, consistent with raised local [Ca ] at the SR Ca pump via RyR1 Ca leak. We also show that basal RyR Ca leak and the heat generated by the SR Ca pump in the absence of RyR Ca leak is greater in fibers from mice than from toads. The distinct function of RyRs and SR Ca pump in endothermic mammals compared to ectothermic amphibians provides insights into the mechanisms by which mammalian skeletal muscle achieves thermogenesis at rest.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2119203119