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

Abstract
Article and author information
Metrics

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 K_ATP 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

M Gartz Hanson

Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, United States

Competing interests
The authors declare that no competing interests exist.
Jonathan J Wilde

Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, United States

Competing interests
The authors declare that no competing interests exist.
Rosa L Moreno

Department of Physiology, University of Colorado, Anschutz Medical Campus, Aurora, United States

Competing interests
The authors declare that no competing interests exist.
Angela D Minic

Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, United States

Competing interests
The authors declare that no competing interests exist.
Lee Niswander

Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, United States

For correspondence
Lee.Niswander@ucdenver.edu

Competing interests
The authors declare that no competing interests exist.

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.

Copyright

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.