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Elife. 2015 Jan 7;4. doi: 10.7554/eLife.02923.

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

Author information

1
Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, United States.
2
Department of Physiology, University of Colorado, Anschutz Medical Campus, Aurora, United States.

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.

KEYWORDS:

KATP channel; cell biology; congenital myopathy; human; mouse; potassium homeostasis; ryanodine receptor

PMID:
25564733
PMCID:
PMC4309926
DOI:
10.7554/eLife.02923
[Indexed for MEDLINE]
Free PMC Article

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