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

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.

• Authors: M Gartz Hanson, Jonathan J Wilde, Rosa L Moreno, Angela D Minic, Lee Niswander
• Journal: eLife (Elife) Vol. 4 (Jan 07 2015) ISSN: 2050-084X [Electronic] England
• PMID: 25564733 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• KATP Channels
• RNA, Messenger
• Ryanodine Receptor Calcium Release Channel
• NAD
• Ethylnitrosourea
• Potassium
• Glyburide
• Calcium

Topics

• Animals
• Biological Transport (drug effects)
• Biomarkers (metabolism)
• Biopsy
• Calcium (metabolism)
• Diet
• Ethylnitrosourea
• Gene Expression Regulation (drug effects)
• Glyburide (pharmacology)
• Heterozygote
• Homeostasis (drug effects)
• Humans
• KATP Channels (metabolism)
• Mice, Inbred C57BL
• Mitochondria (drug effects, metabolism, ultrastructure)
• Muscle, Skeletal (drug effects, pathology, ultrastructure)
• Muscular Diseases (genetics, pathology)
• Mutation (genetics)
• Myopathy, Central Core (genetics, pathology)
• NAD (metabolism)
• Phenotype
• Potassium (metabolism)
• RNA, Messenger (genetics, metabolism)
• Ryanodine Receptor Calcium Release Channel (genetics, metabolism)