Increased basal metabolic rate in mice susceptible to malignant hyperthermia and heat stroke: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle

Ryanodine receptor type-1 (RYR1) and Calsequestrin-1 (CASQ1) proteins, located in the sarcoplasmic reticulum (SR), are two of the main players in skeletal excitation–contraction (EC) coupling. Mutations in the human RYR1 gene (encoding for the SR Ca²⁺ release channel) and ablation in mice of CASQ1 (a SR Ca²⁺ binding protein) cause hypersensitivity to halogenated anesthetics (malignant hyperthermia [MH] susceptibility) and to heat (heat stroke; HS). As both MH and HS are characterized by excessive cytosolic Ca²⁺ levels and hypermetabolic responses, we studied the metabolism of 4-mo-old mice from two different lines that are MH/HS susceptible: knock-in mice carrying a human MH mutation (RYR1^YS) and CASQ1-knockout (ko) mice. RYR1^YS and, to a lesser degree, CASQ1-null mice show an increased volume of oxygen consumption (VO₂) and a lower respiratory quotient (RQ) compared with WT mice (indicative of a metabolism that relies more on lipids). This finding is accompanied by a reduction in total body fat mass in both Y522S and CASQ1-null mice (again, compared with WT). In addition, we found that RYR1^YS and CASQ1-null mice have an increased food consumption (+26.04% and +25.58% grams/day, respectively) and higher basal core temperature (+0.57°C and +0.54°C, respectively) compared with WT mice. Finally, Western blots and electron microscopy indicated that, in hyperthermic mice, (1) SERCA (used to remove myoplasmic Ca²⁺) and UCP3 (responsible for a thermogenic process that dissipates mitochondrial H⁺ gradient) are overexpressed, and (2) mitochondrial volume and percentage of damaged mitochondria are both increased. In conclusion, the MH/HS phenotype in RYR1^YS and CASQ1-null mice is associated with an intrinsically increased basal metabolism.