Ryanodine receptor leak triggers fiber Ca 2+ redistribution to preserve force and elevate basal metabolism in skeletal muscle.

Autor: Lamboley CR; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia., Pearce L; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia., Seng C; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia., Meizoso-Huesca A; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia., Singh DP; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia., Frankish BP; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia., Kaura V; Leeds Institute of Medical Research, University of Leeds, Leeds, UK., Lo HP; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia., Ferguson C; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia., Allen PD; Leeds Institute of Medical Research, University of Leeds, Leeds, UK., Hopkins PM; Leeds Institute of Medical Research, University of Leeds, Leeds, UK., Parton RG; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.; Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, QLD, Australia., Murphy RM; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.; Department of Physiology Anatomy and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia., van der Poel C; Department of Physiology Anatomy and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia., Barclay CJ; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia., Launikonis BS; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2021 Oct 29; Vol. 7 (44), pp. eabi7166. Date of Electronic Publication: 2021 Oct 27.
DOI: 10.1126/sciadv.abi7166
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: