{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T03:06:58Z","timestamp":1784689618271,"version":"3.55.0"},"reference-count":45,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:p>\n                    Pathogenic variants in\n                    <jats:italic>HMGCR<\/jats:italic>\n                    were recently linked to a limb\u2010girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin\u2010associated myopathy (SAM) and autoimmune anti\u2010HMGCR myopathy, are not inherited in a Mendelian pattern. Statins inhibit HMGCR activity to generate their cholesterol\u2010lowering effects and are known to cause multiple types of adverse effects on skeletal muscle, while the antibodies associated with anti\u2010HMGCR myopathy specifically target this enzyme. The mechanism linking pathogenic variants in\n                    <jats:italic>HMGCR<\/jats:italic>\n                    with skeletal muscle dysfunction is unclear. We knocked down\n                    <jats:italic>Hmgcr<\/jats:italic>\n                    in mouse skeletal myoblasts, knocked down\n                    <jats:italic>hmgcr<\/jats:italic>\n                    in Drosophila, and expressed three pathogenic\n                    <jats:italic>HMGCR<\/jats:italic>\n                    variants (c.1327C&gt;T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G&gt;A, p.Ala541Thr) in\n                    <jats:italic>Hmgcr<\/jats:italic>\n                    knockdown mouse myoblasts.\n                    <jats:italic>Hmgcr<\/jats:italic>\n                    deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of\n                    <jats:italic>Hmgcr<\/jats:italic>\n                    knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle\u2010specific knockdown of\n                    <jats:italic>hmgcr<\/jats:italic>\n                    in Drosophila led to lethality. Overexpression of reference\n                    <jats:italic>HMGCR<\/jats:italic>\n                    cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of\n                    <jats:italic>HMGCR<\/jats:italic>\n                    cDNA did not. These results suggest that the three HMGCR\u2010related muscle diseases share disease mechanisms related to skeletal muscle development.\n                  <\/jats:p>","DOI":"10.1111\/febs.17406","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T01:47:24Z","timestamp":1737078444000},"page":"4854-4869","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Effects of\n                    <scp>HMG CoA<\/scp>\n                    reductase (\n                    <scp>HMGCR<\/scp>\n                    ) deficiency on skeletal muscle development"],"prefix":"10.1111","volume":"292","author":[{"given":"Mekala","family":"Gunasekaran","sequence":"first","affiliation":[{"name":"Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology University of Minnesota Medical School  Minneapolis MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah R.","family":"Littel","sequence":"additional","affiliation":[{"name":"Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology University of Minnesota Medical School  Minneapolis MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalya M.","family":"Wells","sequence":"additional","affiliation":[{"name":"Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology University of Minnesota Medical School  Minneapolis MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnnie","family":"Turner","sequence":"additional","affiliation":[{"name":"Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology University of Minnesota Medical School  Minneapolis MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloriana","family":"Campos","sequence":"additional","affiliation":[{"name":"Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology University of Minnesota Medical School  Minneapolis MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sree","family":"Venigalla","sequence":"additional","affiliation":[{"name":"Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology University of Minnesota Medical School  Minneapolis MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elicia A.","family":"Estrella","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Partha S.","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey L.","family":"Daugherty","sequence":"additional","affiliation":[{"name":"Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology University of Minnesota Medical School  Minneapolis MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth A.","family":"Stafki","sequence":"additional","affiliation":[{"name":"Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology University of Minnesota Medical School  Minneapolis MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis M.","family":"Kunkel","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Reghan","family":"Foley","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch National Institute of Neurological Disorders and Stroke, NIH  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Donkervoort","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch National Institute of Neurological Disorders and Stroke, NIH  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten G.","family":"B\u00f6nnemann","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch National Institute of Neurological Disorders and Stroke, NIH  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Toledo\u2010Bravo de Laguna","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Hospital Materno\u2010Infantil  Las Palmas de Gran Canaria Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Nascimento","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology Hospital Sant Joan de D\u00e9u  Barcelona Spain"},{"name":"Applied Research in Neuromuscular Diseases Institut de Recerca Sant Joan de D\u00e9u  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Natera\u2010de Benito","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology Hospital Sant Joan de D\u00e9u  Barcelona Spain"},{"name":"Applied Research in Neuromuscular Diseases Institut de Recerca Sant Joan de D\u00e9u  Barcelona 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