Abstract
Myopathies decrease muscle functionality. Mutations in ryanodine receptor 1 (RyR1) are often associated with myopathies with microscopic core-like structures in the muscle fiber. In this study, we identify a mouse RyR1 model in which heterozygous animals display clinical and pathological hallmarks of myopathy with core-like structures. The RyR1 mutation decreases sensitivity to activated calcium release and myoplasmic calcium levels, subsequently affecting mitochondrial calcium and ATP production. Mutant muscle shows a persistent potassium leak and disrupted expression of regulators of potassium homeostasis. Inhibition of KATP channels or increasing interstitial potassium by diet or FDA-approved drugs can reverse the muscle weakness, fatigue-like physiology and pathology. We identify regulators of potassium homeostasis as biomarkers of disease that may reveal therapeutic targets in human patients with myopathy of central core disease (CCD). Altogether, our results suggest that amelioration of potassium leaks through potassium homeostasis mechanisms may minimize muscle damage of myopathies due to certain RyR1 mutations.
Highlights
Myopathies due to mutations in ryanodine receptor type 1 (RyR1) are inherited and currently incurable
RyR1 mutations in humans are associated with several congenital myopathies including central core disease (CCD), multi-mini core disease, hypokalemic periodic paralysis, and malignant hyperthermia (MH) (Fujii et al, 1991; Marchant et al, 2004; Jungbluth, 2007; Treves et al, 2008; Wilmshurst et al, 2010). 1-month, 2-month, and 1-year old Ryr1AG/+ mice showed a significant decrease in grip strength and considerable deficits on a wire hanging task compared to Ryr1+/+ mice (Figure 1B,C)
Malignant hyperthermia test was performed by placing Ryr1+/+ and Ryr1AG/+ mice in a 41°C humidified incubator for 30 min
Summary
Myopathies due to mutations in RyR1 are inherited and currently incurable. Congenital myopathies are characterized by hypotonia and delay of motor development with weakness in skeletal muscles. Nuclei are located at the periphery of the myofibers and the mitochondria reside throughout the myofiber. Muscle biopsies of patients with myopathies and mutations in ryanodine receptor type 1 (RyR1) show centralized nuclei as well as disorganized areas in the center of the myofiber, called cores, that lack mitochondria and are devoid of metabolic activity, reflective of cellular damage. The most common RyR1-associated myopathy is central core disease (CCD) (Wu et al, 2006; Jungbluth, 2007). RyR1 mutations in muscle cause diseases such as multi-mini core disease (MMD), hypokalemic periodic paralysis, and malignant hyperthermia (MH), the phenotype/genotype relationship is unclear (Fujii et al, 1991; Marchant et al, 2004; Treves et al, 2008; Wilmshurst et al, 2010)
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