Eccentric contractions protect skeletal muscle from temperature‐induced contracture in Y522S RyR1 knock‐in mice

Abstract

Mice with a malignant hyperthermia mutation (Y522S) of the ryanodine receptor (RyR1) can exhibit muscle contracture and die when exposed to elevated temperature. When stressed by elevated temperature (T), Ca2+ leak from the Y522S RyR1 and cellular accumulation is thought to produce reactive nitrogen species that modifies RyR1 resulting in sustained Ca2+ release and muscle contracture. Eccentric contractions are known to reduce muscle strength by impairing voltage‐gated Ca2+ release from RyR1. The purpose of this study was to determine if eccentric contraction‐induced injury would reduce contractures when EDL muscle from Y522S mice is incubated at 35°C. Anterior crural muscles from wild‐type (WT) and Y522S mice were injured by performing 150 eccentric contractions in vivo. EDL muscle function was assessed via force‐frequency (F‐F) experiments at 30 and 35°C 3 and 14 d post‐injury. At 30°C, uninjured EDL from Y522S mice exhibited stable resting force during the F‐F experiment, and peak force at 300 Hz (Po) was not different than WT mice. At 35°C, increases in resting force in Y522S mice at 3 (38%) and 14 (152%) d after injury were less than increases in uninjured muscle (322%). T‐induced decreases in Po in Y522S mice at 3 (34%) and 14 (36%) d were less than in uninjured muscle (65%). Eccentric contractions attenuate T‐induced contractures and reductions in active force in Y522S mice.Supported by NIH grant AR41802