Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

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.

Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation

“…Gene expression analysis was done as described previously 34 . Total RNA was extracted from WT and DG TA muscles using TRIzol reagent and reverse transcribed into cDNA using the iScript cDNA Synthesis Kit.…”

“…Gene expression analysis was done as described previously. 34 Total RNA was extracted from WT and DG TA muscles using TRIzol reagent and reverse transcribed into cDNA using the iScript cDNA Synthesis Kit. Gene expression assay were done with iQ SYBR Green Supermix (Bio-Rad) using a ViiA 7 RT-PCR System (Applied Biosystems).…”

Lactate Fluxes and Plasticity of Adipose Tissues: A Redox Perspective

“…The alteration of lactate-UCP1 signaling has physiopathological consequences, as the inhibition of lactate production through interferon regulatory factor-3 (IRF3)-mediated inhibition of lactate dehydrogenase contributes to the downregulation of UCP1 expression and thermogenesis, in an inflammatory context ( Yan et al, 2021 ). Recently, in a mouse model exhibiting a mutation in the skeletal muscle Ca 2+ release channel (i.e., RYR1) that induces malignant hyperthermia, an increased production of lactate in muscle is involved in the beiging of white adipose tissue and the activation of brown adipose tissue in an MCT1-dependent manner, which would actively contribute to the hyperthermic phenotype ( Wang et al, 2020a ). Together, these recent studies highlight the physiological and pathological importance of lactate-induced beiging.…”

From Mice to Humans: An Overview of the Potentials and Limitations of Current Transgenic Mouse Models of Major Muscular Dystrophies and Congenital Myopathies

“…Apparently, the detailed understanding of the pathomechanism of MH required genetically modified mouse models covering all three hotspots. To date, four MHS RyR1 knock-in muse genotypes are available: Y524S, R163C, G2435R, and T4826I [ 169 , 172 , 230 , 242 , 243 , 244 , 245 ]. All these mice reproduce a typical MHS phenotype, displaying whole body contractions and elevated core temperatures in response to therapeutic concentrations of halothane or isoflurane.…”

“…Homozygous mice show severe skeletal and muscular abnormalities and die at the early stage of intrauterine life (17th day) or soon after birth. Heterozygous mice are viable and reproductive [ 169 , 242 , 243 ]. R163C (also R163C in human) is a dominant heterozygous mutation with no phenotype until exposed to a trigger agent.…”