Potassium dependent rescue of a myopathy with core-like structures in mouse

Abstract

Myopathies decrease muscle functionality. Mutations in ryanodine receptor 1 (RyRl) are often asso< with myopathies with microscopic core-like structures in the muscle fiber. Here we identify a mouse RyRl model in which heterozygous animals display clinical and pathological hallmarks of myopathj core-like structures. The RyRl mutation decreases sensitivity to activated calcium release and myoplasmic calcium levels, subsequently affecting mitochondrial calcium and ATP production. Mut 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-approvi drugs can reverse the muscle weakness, fatigue-like physiology and pathology. We identify regulatoi potassium homeostasis as biomarkers of disease that may reveal therapeutic targets in human patiei 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 RyRl mutations.