ArticleThe Journal of general physiology2011
Muscle weakness in Ryr1I4895T/WT knock-in mice as a result of reduced ryanodine receptor Ca2+ ion permeation and release from the sarcoplasmic reticulum.
Article in The Journal of general physiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 77 citations in OpenAlex.
- The effect of Astym® Therapy on muscle strength: a blinded, randomized, clinically controlled trial.BMC musculoskeletal disorders · 2015Trial
- Molecular Insights into Central Core Disease: Proteomic Signatures and Potential Therapeutic Biomarkers in RYR1 I4895T Mice.International journal of molecular sciences · 2025Article
- Pirfenidone treatment improves ischemic muscle function in mice with chronic kidney disease.Skeletal muscle · 2025Article
- Phosphorylation of RYR1 at SerScience signaling · 2025Article
- Limited pre-clinical relevance of the heterozygous RYR1-I4895T/+ mouse model due to its mild phenotype.Journal of neuromuscular diseases · 2025Article
- Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice.Annals of neurology · 2025Article
- An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease.The EMBO journal · 2024Article
- Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches.Disease models & mechanisms · 2024Review
- CaHandbook of experimental pharmacology · 2023Article
- Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies.The Journal of general physiology · 2022Review
- Postdevelopmental knockout of Orai1 improves muscle pathology in a mouse model of Duchenne muscular dystrophy.The Journal of general physiology · 2022Article
- Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature.Skeletal muscle · 2020Review
- Pre-assembled Ca2+ entry units and constitutively active Ca2+ entry in skeletal muscle of calsequestrin-1 knockout mice.The Journal of general physiology · 2020Article
- Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of works published 1990-2019.Orphanet journal of rare diseases · 2020Article
- Single-channel properties of skeletal muscle ryanodine receptor pore ΔCell calcium · 2020Article
- Single Amino Acid Changes in the Ryanodine Receptor in the Human Population Have EffectsFrontiers in genetics · 2020Article
- Cored in the act: the use of models to understand core myopathies.Disease models & mechanisms · 2019Review
- Article
- A central core disease mutation in the CaAmerican journal of physiology. Cell physiology · 2019Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
The type 1 isoform of the ryanodine receptor (RYR1) is the Ca(2+) release channel of the sarcoplasmic reticulum (SR) that is activated during skeletal muscle excitation-contraction (EC) coupling. Mutations in the RYR1 gene cause several rare inherited skeletal muscle disorders, including malignant hyperthermia and central core disease (CCD). The human RYR1(I4898T) mutation is one of the most common CCD mutations. To elucidate the mechanism by which RYR1 function is altered by this mutation, we characterized in vivo muscle strength, EC coupling, SR Ca(2+) content, and RYR1 Ca(2+) release channel function using adult heterozygous Ryr1(I4895T/+) knock-in mice (IT/+). Compared with age-matched wild-type (WT) mice, IT/+ mice exhibited significantly reduced upper body and grip strength. In spite of normal total SR Ca(2+) content, both electrically evoked and 4-chloro-m-cresol-induced Ca(2+) release were significantly reduced and slowed in single intact flexor digitorum brevis fibers isolated from 4-6-mo-old IT/+ mice. The sensitivity of the SR Ca(2+) release mechanism to activation was not enhanced in fibers of IT/+ mice. Single-channel measurements of purified recombinant channels incorporated in planar lipid bilayers revealed that Ca(2+) permeation was abolished for homotetrameric IT channels and significantly reduced for heterotetrameric WT:IT channels. Collectively, these findings indicate that in vivo muscle weakness observed in IT/+ knock-in mice arises from a reduction in the magnitude and rate of RYR1 Ca(2+) release during EC coupling that results from the mutation producing a dominant-negative suppression of RYR1 channel Ca(2+) ion permeation.
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