Pantothenate kinase 4 controls skeletal muscle substrate metabolism

Adriana Miranda-Cervantes, Andreas M. Fritzen, Steffen H. Raun, Ondřej Hodek, Lisbeth L. V. Møller, Kornelia Johann, Luisa Deisen, Paul Gregorevic, Anders Gudiksen, Anna Artati, Jerzy Adamski, Nicoline R. Andersen, Casper M. Sigvardsen, Christian S. Carl, Christian T. Voldstedlund, Rasmus Kjøbsted, Stefanie M. Hauck, Peter Schjerling, Thomas E. Jensen, Alberto Cebrian-Serrano, Markus Jähnert, Pascal Gottmann, Ingo Burtscher, Heiko Lickert, Henriette Pilegaard, Annette Schürmann, Matthias H. Tschöp, Thomas Moritz, Timo D. Müller, Lykke Sylow, Bente Kiens, Erik A. Richter and Maximilian Kleinert ()
Additional contact information
Adriana Miranda-Cervantes: Potsdam-Rehbruecke
Andreas M. Fritzen: University of Copenhagen
Steffen H. Raun: University of Copenhagen
Ondřej Hodek: Swedish University of Agricultural Sciences
Lisbeth L. V. Møller: University of Copenhagen
Kornelia Johann: Potsdam-Rehbruecke
Luisa Deisen: Potsdam-Rehbruecke
Paul Gregorevic: University of Melbourne
Anders Gudiksen: University of Copenhagen
Anna Artati: Ingolstädter Landstr. 1
Jerzy Adamski: Ingolstädter Landstraße 1
Nicoline R. Andersen: University of Copenhagen
Casper M. Sigvardsen: University of Copenhagen
Christian S. Carl: University of Copenhagen
Christian T. Voldstedlund: University of Copenhagen
Rasmus Kjøbsted: University of Copenhagen
Stefanie M. Hauck: German Center for Diabetes Research (DZD)
Peter Schjerling: Copenhagen University Hospital - Bispebjerg-Frederiksberg
Thomas E. Jensen: University of Copenhagen
Alberto Cebrian-Serrano: German Center for Diabetes Research (DZD)
Markus Jähnert: German Center for Diabetes Research (DZD)
Pascal Gottmann: German Center for Diabetes Research (DZD)
Ingo Burtscher: German Center for Diabetes Research (DZD)
Heiko Lickert: German Center for Diabetes Research (DZD)
Henriette Pilegaard: University of Copenhagen
Annette Schürmann: German Center for Diabetes Research (DZD)
Matthias H. Tschöp: German Center for Diabetes Research (DZD)
Thomas Moritz: Swedish University of Agricultural Sciences
Timo D. Müller: German Center for Diabetes Research (DZD)
Lykke Sylow: University of Copenhagen
Bente Kiens: University of Copenhagen
Erik A. Richter: University of Copenhagen
Maximilian Kleinert: Potsdam-Rehbruecke

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-024-55036-w

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