Basic Skeletal Muscle Phenotype of a Knock-in Mouse Model of Malignant Hyperthermia

Abstract

Malignant hyperthermia (MH) is an inheritable disorder that can result in skeletal muscle hypermetabolism, limb rigidity, body temperature elevation, and death after exposure to halogenated anesthetics. Gene mutations of the skeletal muscle ryanodine receptor (i.e., SR Ca2+ release channel, or RYR1) have been associated with MH in humans. Recently, the first mouse model of MH was created in which tyrosine 522 was replaced with serine (Y522S) in RYR1. The heterozygous expression of the Y522S mutation mimics an autosomal dominant condition in humans. PURPOSE: To describe basic skeletal muscle morphology and contractile characteristics in Y522S and wild-type (WT) control mice. METHODS: Isometric torque as a function of stimulation frequency (20–400Hz) was measured in vivo from the anterior crural muscles of anesthetized Y522S (n = 15) and WT (n = 4) mice. In vivo twitch potentiation was measured at 20 Hz. The sensitivity of the EDL muscle to caffeine (0-50 mM) was assessed in vitro at 30 degrees C. RESULTS: There were no differences between Y522S and WT mice for body weight (24.9+ 1.0 vs. 22.5+ 1.4 g), wet weight of the tibialis anterior (42.8 + 1.5 vs. 41.4 + 3.4 g) and extensor digitorum longus (9.4 + 0.5 vs. 8.7 + 0.8 g) muscles, or isometric torque as a function of stimulation frequency. However, anterior crural muscles from Y522S mice did exhibit 25.1 + 1% potentiation of twitches at 20 Hz stimulation, whereas WT mice displayed none (−8.0 + 2.3%). EDL muscles from Y522S mice were more sensitive to caffeine than WT mice, with peak baseline isometric forces being greater for Y522S mice at caffeine concentrations greater than 4 mM. CONCLUSION: Anterior crural skeletal muscles from Y522S mice appear similar to WT control mice in size and isometric strength. However, anterior crural skeletal muscles of Y522S mice exhibit twitch potentiation and have a greater sensitivity to caffeine than WT controls.