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Miranda-Cervantes A, Fritzen AM, Raun SH, Hodek O, Møller LLV, Johann K, Deisen L, Gregorevic P, Gudiksen A, Artati A, Adamski J, Andersen NR, Sigvardsen CM, Carl CS, Voldstedlund CT, Kjøbsted R, Hauck SM, Schjerling P, Jensen TE, Cebrian-Serrano A, Jähnert M, Gottmann P, Burtscher I, Lickert H, Pilegaard H, Schürmann A, Tschöp MH, Moritz T, Müller TD, Sylow L, Kiens B, Richter EA, Kleinert M
Nat Commun 16 (1) 345 [2025-01-02; online 2025-01-02]
Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. 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.
Swedish Metabolomics Centre [Collaborative]
PubMed 39746949
DOI 10.1038/s41467-024-55036-w
Crossref 10.1038/s41467-024-55036-w
pmc: PMC11695632
pii: 10.1038/s41467-024-55036-w