title: 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.affiliation: Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, United States.
authors.forename: M Gartz
authors.initials: MG
authors.lastname: Hanson
authors.affiliation: Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, United States.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Wilde
authors.affiliation: Department of Physiology, University of Colorado, Anschutz Medical Campus, Aurora, United States.
authors.forename: Rosa L
authors.initials: RL
authors.lastname: Moreno
authors.affiliation: Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, United States.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Minic
authors.affiliation: Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, United States.
authors.forename: Lee
authors.initials: L
authors.lastname: Niswander
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002118:Calcium / Q000378:metabolism; D004032:Diet; D005038:Ethylnitrosourea; D005786:Gene Expression Regulation / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006579:Heterozygote; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D054086:KATP Channels / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000235:genetics / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D020512:Myopathy, Central Core / Q000235:genetics / Q000473:pathology; D009243:NAD / Q000378:metabolism; D010641:Phenotype; D011188:Potassium / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D054086:KATP Channels; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D009243:NAD; D005038:Ethylnitrosourea; D011188:Potassium; D005905:Glyburide; D002118:Calcium
keywords: KATP channel; cell biology; congenital myopathy; human; mouse; potassium homeostasis; ryanodine receptor