TY - JOUR
T1 - Pantothenate kinase 4 controls skeletal muscle substrate metabolism
AU - Miranda-Cervantes, Adriana
AU - Fritzen, Andreas M.
AU - Raun, Steffen H.
AU - Hodek, Ondřej
AU - Møller, Lisbeth L. V.
AU - Johann, Kornelia
AU - Deisen, Luisa
AU - Gregorevic, Paul
AU - Gudiksen, Anders
AU - Artati, Anna
AU - Adamski, Jerzy
AU - Andersen, Nicoline R.
AU - Sigvardsen, Casper M.
AU - Carl, Christian S.
AU - Voldstedlund, Christian T.
AU - Kjøbsted, Rasmus
AU - Hauck, Stefanie M.
AU - Schjerling, Peter
AU - Jensen, Thomas E.
AU - Cebrian-Serrano, Alberto
AU - Jähnert, Markus
AU - Gottmann, Pascal
AU - Burtscher, Ingo
AU - Lickert, Heiko
AU - Pilegaard, Henriette
AU - Schürmann, Annette
AU - Tschöp, Matthias H.
AU - Moritz, Thomas
AU - Müller, Timo D.
AU - Sylow, Lykke
AU - Kiens, Bente
AU - Richter, Erik A.
AU - Kleinert, Maximilian
N1 - © 2025. The Author(s).
PY - 2025
Y1 - 2025
N2 - 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.
AB - 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.
KW - Muscle, Skeletal/metabolism
KW - Animals
KW - Glucose/metabolism
KW - Phosphotransferases (Alcohol Group Acceptor)/metabolism
KW - Acetyl Coenzyme A/metabolism
KW - Lipid Metabolism
KW - Mice
KW - Malonyl Coenzyme A/metabolism
KW - Male
KW - Oxidation-Reduction
KW - Mice, Knockout
KW - Fatty Acids/metabolism
KW - Glycolysis
KW - Mice, Inbred C57BL
KW - Physical Conditioning, Animal
KW - Insulin/metabolism
KW - Glucose Intolerance/metabolism
U2 - 10.1038/s41467-024-55036-w
DO - 10.1038/s41467-024-55036-w
M3 - Journal article
C2 - 39746949
VL - 16
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 345
ER -