Malignant Hyperthermia Susceptible Mice Can Safely Perform Voluntary Endurance Training And Exhibit An Intrinsic Fatigue Resistance

Abstract

Malignant hyperthermia (MH) is a potentially lethal skeletal muscle disorder in which uncontrolled SR Ca++ release is induced by halogenated anesthetics, heat, and potentially endurance exercise. PURPOSE: To determine if MH susceptible mice (Y522S; heterozygous expression of ryanodine receptor 1 Y522S mutation) can perform 6 weeks of voluntary wheel running without inducing a fatal MH episode or excessive muscle damage and to assess the adaptive potential of Y522S anterior crural muscles [tibialis anterior (TA) and extensor digitorum longus (EDL) muscles]. METHODS: Wild type (WT) and Y522S mice were housed (∼22°C) individually with a running wheel, while age-matched sedentary mice served as controls (n = 8/group). Trained and sedentary mice performed an in vivo anterior crural muscle fatigue test (360 concentric contractions in 30 minutes; 300 Hz, 38° angular movement at 400°/s). Citrate synthase activity and cytochrome C oxidase (COXIV subunit) protein content were determined in TA and EDL muscles respectively. RESULTS: Y522S mice voluntarily ran without inducing a fatal MH episode, but ran 42% less distance per day than WT mice (4.0±1.1 vs 6.9±1.0 km/d). Neither Y522S nor WT trained mice exhibited exacerbated histological signs (H&E stain; right TA) of muscle damage. Sedentary Y522S mice exhibited a greater intrinsic fatigue resistance than WT mice (fatigue index: -13.4±2.7 vs -28.9±3.1%), as well as a ∼67% greater EDL muscle COXIV protein content. Additionally, citrate synthase activity was greater in Y522S than WT TA muscle (28.1±0.9 vs 26.0±0.6 µmol/min/g wet weight), regardless of training status. Wheel running improved fatigability (WT & Y522S fatigue index: -19.2±1.6 & -12.0±1.3%) and increased COXIV protein content (WT & Y522S: ∼57 & ∼17%) in WT but not Y522S mice. Trained Y522S mice remained more fatigue resistant than WT mice, although COXIV protein content was similar between groups after training. CONCLUSION: Y522S mice can run voluntarily in an environment that is not thermally stressful (i.e., ∼22°C) without inducing a MH episode and have an enhanced intrinsic resistance to fatigue, which may partially stem from a greater aerobic capacity. -Supported by NIH grant AR41802