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Although RYR1 dysfunction is the primary mechanism in <jats:italic>RYR1<\/jats:italic>\u2010related disorders, other downstream pathogenic events are less well understood and may include a secondary remodeling of major contractile proteins. Hence, in the present study, we aimed to investigate whether congenital myopathy\u2010related <jats:italic>RYR1<\/jats:italic> mutations alter the regulation of the most abundant contractile protein, myosin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used skeletal muscle tissues from five patients with <jats:italic>RYR1<\/jats:italic>\u2010related congenital myopathy and compared those with five controls and five patients with <jats:italic>RYR1<\/jats:italic>\u2010related rhabdomyolysis\/myalgia. We then defined post\u2010translational modifications on myosin heavy chains (MyHCs) using LC\/MS. In parallel, we determined myosin relaxed states using Mant\u2010ATP chase experiments and performed molecular dynamics (MD) simulations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LC\/MS revealed two additional phosphorylations (Thr1309\u2010P and Ser1362\u2010P) and one acetylation (Lys1410\u2010Ac) on the \u03b2\/slow MyHC of patients with congenital myopathy. This method also identified six acetylations that were lacking on MyHC type IIa of these patients (Lys35\u2010Ac, Lys663\u2010Ac, Lys763\u2010Ac, Lys1171\u2010Ac, Lys1360\u2010Ac, and Lys1733\u2010Ac). MD simulations suggest that modifying myosin Ser1362 impacts the protein structure and dynamics. Finally, Mant\u2010ATP chase experiments showed a faster ATP turnover time of myosin heads in the disordered\u2013relaxed conformation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Altogether, our results suggest that <jats:italic>RYR1<\/jats:italic> mutations have secondary negative consequences on myosin structure and function, likely contributing to the congenital myopathic phenotype.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.14035","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T09:28:14Z","timestamp":1692696494000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Abnormal myosin post\u2010translational modifications and <scp>ATP<\/scp> turnover time associated with human congenital myopathy\u2010related <i>RYR1<\/i> mutations"],"prefix":"10.1111","volume":"239","author":[{"given":"Alexander","family":"Sonne","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Katarina","family":"Antonovic","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Physical and Chemical Sciences Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Melhedegaard","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fariha","family":"Akter","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Physical and Chemical Sciences Queen Mary 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