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

Hui J Wang,Jong Min Choi,Matthew L Baker,Chang Seok Lee,Sung Yun Jung,Linda Groom,Robia G Pautler,Rachel Sue Zhen Yee,Dimitra K Georgiou,Nicol C Voermans ,Robert T Dirksen,Poonam Sarkar,Amy D Hanna,Nadia H Agha,Jin Hee Hong ,Ting Tsung Chang ,Jonathan Romero,Lyle W Babcock ,Sheila Riazi,M Waleed Gaber,Inbar Friedman,Joseph Recio,Susan L Hamilton

doi:10.1038/s41467-020-18865-z

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.

Highlights

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
Human RYR1 mutations that underlie MHS are frequently associated with heat and/or exercise-induced rhabdomyolysis, exercise intolerance, heat-induced muscle cramps, and death[19,38,39,40]
We evaluated the heat sensitivity in human carriers of RYR1 variants that were referred to the Malignant hyperthermia (MH) Investigation Unit (MHIU) at Toronto General Hospital between 1994 and 2019 (Supplementary Data 1)

Summary

Introduction

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. Most mutations that underlie human MHS are in the skeletal muscle Ca2+ release channel (RYR1)[8,9] Triggers such as volatile anesthetics and/or heat cause the uncontrolled release of Ca2+ from the sarcoplasmic reticulum (SR) via RYR1, leading to sustained muscle contractures. The heat-induced episodes, often occur in nonclinical settings where immediate administration of dantrolene is impractical[23] Both anesthetic MH episodes and non-anesthetic MH-like responses to heat are highly variable with respect to probability of occurrence and disease presentation both for a single patient and among family members with the same mutation[6,19]. Similar to human MHS, the MH and MH-like responses of the YS mice are characterized by sustained whole-body muscle contractures which lead to hyperthermia, hyperventilation, rhabdomyolysis and, death[24]

Methods

Results

Conclusion