Publication Date
10-9-2020
Journal
Nature Communications
DOI
10.1038/s41467-020-18865-z
PMID
33037202
PMCID
PMC7547078
PubMedCentral® Posted Date
10-9-2020
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Adipose Tissue, Brown, Adolescent, Adult, Animals, Child, Child, Preschool, Female, Heat-Shock Response, Humans, Infant, Lactates, Male, Malignant Hyperthermia, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Mutation, Retrospective Studies, Ryanodine Receptor Calcium Release Channel, Thermogenesis, Uncoupling Protein 1, Young Adult, Fat metabolism, Calcium and phosphate metabolic disorders
Abstract
Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca2+ driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Integrative Medicine Commons
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