Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during Prolonged Exercise.
Pyruvate dehydrogenase (PDH) plays a key role in the regulation of skeletal muscle substrate utilization. IL-6 is produced in skeletal muscle during exercise in a duration dependent manner and has been reported to increase whole body fatty acid oxidation, muscle glucose uptake and decrease PDHa activity in skeletal muscle of fed mice. The aim of the present study was to examine whether muscle IL-6 contributes to exercise-induced PDH regulation in skeletal muscle. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and floxed littermate controls (control) completed a single bout of treadmill exercise for 10, 60 or 120 min, with rested mice of each genotype serving as basal controls. The respiratory exchange ratio (RER) was overall higher (P<0.05) in IL-6 MKO than control mice during the 120 min of treadmill exercise, while RER decreased during exercise independent of genotype. AMPK and ACC phosphorylation also increased with exercise independent of genotype. PDHa activity was in control mice higher (P<0.05) at 10 and 60 min of exercise than at rest but remained unchanged in IL-6 MKO mice. In addition, PDHa activity was higher (P<0.05) in IL-6 MKO than control mice at rest and 60 min of exercise. Neither PDH phosphorylation nor acetylation could explain the genotype differences in PDHa activity. Together, this provides evidence that skeletal muscle IL-6 contributes to the regulation of PDH at rest and during prolonged exercise and suggests that muscle IL-6 normally dampens carbohydrate utilization during prolonged exercise via effects on PDH.
Section for cell biology and physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Anders
A
Gudiksen
Section for cell biology and physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Camilla Lindgren
CL
Schwartz
Section for cell biology and physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Lærke
L
Bertholdt
Section for cell biology and physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Ella
E
Joensen
Section for cell biology and physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Jakob G
JG
Knudsen
Section for cell biology and physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Henriette
H
Pilegaard
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002151:Calorimetry; D019069:Cell Respiration; D005227:Fatty Acids / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007773:Lactates / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010766:Phosphorylation; D010805:Physical Conditioning, Animal; D010807:Physical Endurance; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012146:Rest; D050796:STAT3 Transcription Factor / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D005227:Fatty Acids; D015850:Interleukin-6; D007773:Lactates; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D019298:Glucose-6-Phosphate; D006003:Glycogen; D030481:Pyruvate Dehydrogenase (Lipoamide); D006593:Hexokinase; D000263:Adenylate Kinase; D056566:Sirtuin 3; D000103:Acetyl-CoA Carboxylase