Ryanodine receptor leak triggers fiber Ca²⁺ redistribution to preserve force and elevate basal metabolism in skeletal muscle.

Abstract

Muscle contraction depends on tightly regulated Ca²⁺ release. Aberrant Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ leak initiates a cascade of events that cause precise redistribution of Ca²⁺ among the SR, cytoplasm, and mitochondria through altering the Ca²⁺ permeability of the transverse tubular system membrane. This redistribution of Ca²⁺ allows mice with moderate RyR1 leak to maintain normal function; however, severe RyR1 leak with <i>RYR1</i> 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 <i>RYR1</i> mutations.