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Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a new conserved exercise target with high abundance in muscle. Muscle-specific deletion of PanK4 impairs fatty acid oxidation which is related to higher intramuscular acetyl-CoA and malonyl-CoA levels. Elevated acetyl-CoA levels persist regardless of feeding state and are associated with whole-body glucose intolerance, reduced insulin-stimulated glucose uptake in glycolytic muscle, and impaired glucose uptake during exercise. Conversely, increasing PanK4 levels in glycolytic muscle lowers acetyl-CoA and enhances glucose uptake. Our findings highlight PanK4 as an important regulator of acetyl-CoA levels, playing a key role in both muscle lipid and glucose metabolism.<\/jats:p>","DOI":"10.1038\/s41467-024-55036-w","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T03:40:35Z","timestamp":1735875635000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Pantothenate kinase 4 controls skeletal muscle substrate metabolism"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8170-5101","authenticated-orcid":false,"given":"Adriana","family":"Miranda-Cervantes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8793-9739","authenticated-orcid":false,"given":"Andreas M.","family":"Fritzen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen H.","family":"Raun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8307-9575","authenticated-orcid":false,"given":"Ond\u0159ej","family":"Hodek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1885-0102","authenticated-orcid":false,"given":"Lisbeth L. 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KG (2024), AstraZeneca GmbH (2024), Lilly Deutschland GmbH (2024) and Novo Nordisk Pharma GmbH (2024). He is co-founder of the biotech startups Ghrelco and Bluewater Biotech (2024). As CEO and CSO of Helmholtz Munich, M.H.T. is co-responsible for countless collaborations of the employees with a multitude of companies and institutions, worldwide. In this capacity, he discusses potential projects with and has signed\/signs contracts for the centers institute(s) related to research collaborations worldwide, including but not limited to pharmaceutical corporations like Boehringer Ingelheim, Novo Nordisk, Roche Diagnostics, Arbormed, Eli Lilly, SCG Cell Therapy and others. As the CEO of Helmholtz Munich, he was\/is further overall responsible for commercial technology transfer activities. M.H.T. confirms that to the best of his knowledge none of the above funding sources or collaborations were involved in or had an influence on the preparation of this manuscript. 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