{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:03:04Z","timestamp":1791118984526,"version":"4.1.0"},"reference-count":28,"publisher":"National Academy of Sciences","issue":"51","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,12,22]]},"abstract":"<jats:p>\n                    Malignant hyperthermia (MH) and central core disease are related skeletal muscle diseases often linked to mutations in the type 1 ryanodine receptor (RYR1) gene, encoding for the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release channel of the sarcoplasmic reticulum (SR). In humans, the Y522S RYR1 mutation is associated with malignant hyperthermia susceptibility (MHS) and the presence in skeletal muscle fibers of core regions that lack mitochondria. In heterozygous Y522S knock-in mice (RYR1\n                    <jats:sup>Y522S\/WT<\/jats:sup>\n                    ), the mutation causes SR Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak and MHS. Here, we identified mitochondrial-deficient core regions in skeletal muscle fibers from RYR1\n                    <jats:sup>Y522S\/WT<\/jats:sup>\n                    knock-in mice and characterized the structural and temporal aspects involved in their formation. Mitochondrial swelling\/disruption, the initial detectable structural change observed in young-adult RYR1\n                    <jats:sup>Y522S\/WT<\/jats:sup>\n                    mice (2 months), does not occur randomly but rather is confined to discrete areas termed presumptive cores. This localized mitochondrial damage is followed by local disruption\/loss of nearby SR and transverse tubules, resulting in early cores (2\u20134 months) and small contracture cores characterized by extreme sarcomere shortening and lack of mitochondria. At later stages (1 year), contracture cores are extended, frequent, and accompanied by areas in which contractile elements are also severely compromised (unstructured cores). Based on these observations, we propose a possible series of events leading to core formation in skeletal muscle fibers of RYR1\n                    <jats:sup>Y522S\/WT<\/jats:sup>\n                    mice: Initial mitochondrial\/SR disruption in confined areas causes significant loss of local Ca\n                    <jats:sup>2+<\/jats:sup>\n                    sequestration that eventually results in the formation of contractures and progressive degradation of the contractile elements.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0911496106","type":"journal-article","created":{"date-parts":[[2009,12,4]],"date-time":"2009-12-04T22:05:25Z","timestamp":1259964325000},"page":"21996-22001","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":101,"title":["Characterization and temporal development of cores in a mouse model of malignant hyperthermia"],"prefix":"10.1073","volume":"106","author":[{"given":"Simona","family":"Boncompagni","sequence":"first","affiliation":[{"name":"Centro Scienze dell'Invecchiamento, Department of Basic and Applied Medical Sciences, Interuniversity Institute of Myology, Universit\u00e0 Gabriele d'Annunzio, I-66013 Chieti, Italy;"},{"name":"Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann E.","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Micaroni","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Oncology, Telethon Electron Microscopy Core Facility, Consorzio Mario Negri Sud, I-66030 Santa Maria Imbaro (CH), Italy;"},{"name":"Department of Molecular Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane QLD 4072, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Dirksen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Franzini-Armstrong","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feliciano","family":"Protasi","sequence":"additional","affiliation":[{"name":"Centro Scienze dell'Invecchiamento, Department of Basic and Applied Medical Sciences, Interuniversity Institute of Myology, Universit\u00e0 Gabriele d'Annunzio, I-66013 Chieti, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,12,22]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0143-4160(02)00138-0"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200211000-00007"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.256.5058.789"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/79.4.610"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-2-31"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(60)92665-9"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/84.2.167"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880120203"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/93.1.133"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.38.12.1177"},{"key":"e_1_3_3_11_2","first-page":"497","volume-title":"Proceedings of the Second International Congress on Muscle Diseases","author":"Neville HE","year":"1973","unstructured":"HE Neville, MH Brook, Central core fibers: Structured and unstructured. Proceedings of the Second International Congress on Muscle Diseases, ed B Kakukas (Excerpta Medica, Amsterdam), pp. 497\u2013511, Part 1. (1973)."},{"key":"e_1_3_3_12_2","first-page":"503","article-title":"Central \u201ccore\u201d disease of skeletal muscle. Ultrastructural and cytochemical observations in two cases","volume":"47","author":"Gonatas NK","year":"1965","unstructured":"NK Gonatas, et al., Central \u201ccore\u201d disease of skeletal muscle. Ultrastructural and cytochemical observations in two cases. Am J Pathol 47, 503\u2013524 (1965).","journal-title":"Am J Pathol"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1994.1483"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-4497fje"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.02.042"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0812661106"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.118.3.277"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1050-1738(02)00163-9"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.104.048447"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-07-0783"},{"key":"e_1_3_3_21_2","first-page":"121","volume-title":"Pathology of Skeletal Muscle","author":"Carpenter S","year":"1984","unstructured":"S Carpenter, G Karpati Pathology of Skeletal Muscle (Churchill Livingstone, New York), pp. 121\u2013129 (1984)."},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/99.4.617"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-198709000-00004"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00139.2004"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp126"},{"key":"e_1_3_3_26_2","first-page":"933","article-title":"Regulation by calcium of the contraction and relaxation of muscle fibers","volume":"23","author":"Podolsky RJ","year":"1964","unstructured":"RJ Podolsky, LL Costantin, Regulation by calcium of the contraction and relaxation of muscle fibers. Fed Proc 23, 933\u2013939 (1964).","journal-title":"Fed Proc"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.189.1.1"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-8966(02)00135-9"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0911496106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T18:56:43Z","timestamp":1649789803000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0911496106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,12,22]]},"references-count":28,"journal-issue":{"issue":"51","published-print":{"date-parts":[[2009,12,22]]}},"alternative-id":["10.1073\/pnas.0911496106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0911496106","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,12,22]]},"assertion":[{"value":"2009-07-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-12-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}