{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:09:02Z","timestamp":1768511342337,"version":"3.49.0"},"posted":{"date-parts":[[2024,5,8]]},"group-title":"Developmental Biology","reference-count":46,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Pathogenic variants in\n                  <jats:italic>HMGCR<\/jats:italic>\n                  were recently linked to a limb-girdle 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-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. 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-specific 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-related muscle diseases share disease mechanisms related to skeletal muscle development.\n                <\/jats:p>","DOI":"10.1101\/2024.05.06.591934","type":"posted-content","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T22:05:29Z","timestamp":1715205929000},"source":"Crossref","is-referenced-by-count":2,"title":["Effects of HMGCR deficiency on skeletal muscle development"],"prefix":"10.64898","author":[{"given":"Mekala","family":"Gunasekaran","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah R.","family":"Littel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalya M.","family":"Wells","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johnnie","family":"Turner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gloriana","family":"Campos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sree","family":"Venigalla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elicia A.","family":"Estrella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Partha S.","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audrey L.","family":"Daugherty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seth A.","family":"Stafki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis M.","family":"Kunkel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. 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