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. 2016 Jun 21;11(6):e0156460.
doi: 10.1371/journal.pone.0156460. eCollection 2016.

Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during Prolonged Exercise

Anders Gudiksen  1 , Camilla Lindgren Schwartz  1 , Lærke Bertholdt  1 , Ella Joensen  1 , Jakob G Knudsen  1 , Henriette Pilegaard  1
Affiliations

Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during Prolonged Exercise

Anders Gudiksen et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1
A Running duration (min) in a graded treadmill endurance test and basal skeletal muscle B) HKII and GLUT4 protein content, C) OXPHOS complex (I-V) protein content and D) HAD and CS activity in skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate floxed control (Control) mice. Protein levels are given in arbitrary units (AU). Values are given as mean ± SE; n = 6–10 in A and n = 9–10 in B-D. #: significantly different from control, P<0.05;
Fig 2
Fig 2
A) Plasma IL-6 and skeletal muscle B) IL-6 mRNA, C) SOCS3 mRNA and D) STAT3 Tyr705 phosphorylation in skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate floxed control (Control) mice at rest and after 10, 60 or 120 min of exercise. Protein levels are given in arbitrary units (AU). Values are given as mean ± SE; n = 10. *: significantly different from rest within given genotype, P<0.05. #: significantly different from control within given time point, P<0.05.
Fig 3
Fig 3
A) AMP-activated protein kinase (AMPK) Thr172 phosphorylation and B) Acetyl-CoA carboxylase 2 (ACC2) phosphorylation in skeletal muscle from skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate floxed controls (Control) mice at rest and after 10, 60 or 120 min of exercise. Values are given as mean ± SE; n = 9–10. Phosphorylation levels are given in arbitrary units (AU). *: significantly different from rest within given genotype, P<0.05. #: significantly different from control within given time point, P<0.05. (*): Tendency to be significantly different from rest within given genotype, 0.05<P<0.01.
Fig 4
Fig 4
A) PDH Ser300 phosphorylation, B) PDH Ser232 phosphorylation, C) PDH acetylation in skeletal muscle from skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate floxed controls (Control) at rest and after 10, 60 or 120 min of exercise and D) basal PDK1, PDK2, PDK4 and PDP1. Values are given as mean ± SE; n = 10 in A,B and D and n = 5 in C. *: significantly different from rest within given genotype, P<0.05. #: significantly different from control within given time point, P<0.05.
Fig 5
Fig 5. PDHa activity in skeletal muscle from skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate floxed controls (Control) at rest and after 10, 60 or 120 min of exercise.
Values are given as mean ± SE; n = 10. *: significantly different from rest within given genotype, P<0.05. #: significantly different from control within given time point, P<0.05.
Fig 6
Fig 6. Respiratory Exchange Ratio (RER) in skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate floxed controls (Control) during 120 min of metabolic treadmill exercise.
Values are given as mean ± SE for every 10 minutes of continuous measurements; n = 5–7. *: significantly different from 10 min within given genotype, P<0.05. #: significantly different from control within given time point, P<0.05.
Fig 7
Fig 7. Representative blots of STAT3, STAT3 Tyr705 phosphorylation (phos), AMPK Thr 172 phos, AMPKα2, ACC2 Ser212 phos, ACC2, PDH Ser293 phos, PDH Ser300 phos, PDH Ser232 phos, PDH Ser295 phos, PDH protein, lysine acetylated pdh-E1α protein, sirtuin 3 (SIRT3), Hexokinase II (HKII), GLUT4, OXPHOS complexes I-V, PDK1, PDK2, PDK4 and PDP1 protein content.
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Grants and funding

This work was supported by Lundbeckfonden: R93-2011-8974, www.lundbeckfonden.com/; Danish Agency for Science, Technology and Innovation, DFF-1323-00317, http://ufm.dk/en/the-minister-and-the-ministry/organisation/the-danish-agency-for-science-technology-and-innovation/contact. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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