{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T12:15:43Z","timestamp":1791029743799,"version":"4.1.0"},"reference-count":59,"publisher":"Rockefeller University Press","issue":"1","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,1,1]]},"abstract":"<jats:p>The type 1 isoform of the ryanodine receptor (RYR1) is the Ca2+ release channel of the sarcoplasmic reticulum (SR) that is activated during skeletal muscle excitation\u2013contraction (EC) coupling. Mutations in the RYR1 gene cause several rare inherited skeletal muscle disorders, including malignant hyperthermia and central core disease (CCD). The human RYR1I4898T 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 Ca2+ content, and RYR1 Ca2+ release channel function using adult heterozygous Ryr1I4895T\/+ 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 Ca2+ content, both electrically evoked and 4-chloro-m-cresol\u2013induced Ca2+ release were significantly reduced and slowed in single intact flexor digitorum brevis fibers isolated from 4\u20136-mo-old IT\/+ mice. The sensitivity of the SR Ca2+ 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 Ca2+ 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 Ca2+ release during EC coupling that results from the mutation producing a dominant-negative suppression of RYR1 channel Ca2+ ion permeation.<\/jats:p>","DOI":"10.1085\/jgp.201010523","type":"journal-article","created":{"date-parts":[[2010,12,14]],"date-time":"2010-12-14T22:07:12Z","timestamp":1292364432000},"page":"43-57","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":77,"title":["Muscle weakness in <i>Ryr1I4895T\/WT<\/i> knock-in mice as a result of reduced ryanodine receptor Ca2+ ion permeation and release from the sarcoplasmic reticulum"],"prefix":"10.1085","volume":"137","author":[{"given":"Ryan E.","family":"Loy","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"Orynbayev","sequence":"additional","affiliation":[{"name":"Institute of Applied Physiology, Ulm University, D-89069 Ulm, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoita","family":"Andronache","sequence":"additional","affiliation":[{"name":"Institute of Applied Physiology, Ulm University, D-89069 Ulm, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Apostol","sequence":"additional","affiliation":[{"name":"Institute of Applied Physiology, Ulm University, D-89069 Ulm, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Zvaritch","sequence":"additional","affiliation":[{"name":"Banting and Best Department of Medical Research, University of Toronto, Charles H. 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