Potassium dependent rescue of a myopathy with core-like structures in mouse
- University of Colorado, Anschutz Medical Campus, 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. Here 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.
Article and author information
Author details
Reviewing Editor
- Giulio Cossu, University of Manchester, United Kingdom
Ethics
Animal experimentation: All experiments were conducted in accordance with the protocols described in the Guide for the Care and Use of Laboratory Animals (NIH. Revised 2011). All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (B-69913(10)1D) of the University of Colorado Denver.
Human subjects: Ethical approval was obtained through University of Colorado COMIRB approval for human subject research (protocol number 12-1504). All samples were provided through an exempt IRB which stated that we were disallowed patient information that could be used as an identifier.
Version history
- Received: March 27, 2014
- Accepted: January 7, 2015
- Accepted Manuscript published: January 7, 2015 (version 1)
- Version of Record published: January 29, 2015 (version 2)
- Version of Record updated: March 9, 2017 (version 3)
Copyright
© 2015, Hanson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Potassium dependent rescue of a myopathy with core-like structures in mouse
eLife 4:e02923.
https://doi.org/10.7554/eLife.02923
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