Pantothenate kinase 4 controls skeletal muscle substrate metabolism
Abstract
AbstractMetabolic 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.
Article Details
Authors (33)
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
Metabolomics and Proteomics Core, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.
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
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Timo D. Müller
Lykke Sylow
Bente Kiens
Erik A. Richter
Maximilian Kleinert