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

Anders Gudiksen,Lærke Bertholdt,Jakob G Knudsen,Henriette Pilegaard,Ella Joensen,Camilla Lindgren Schwartz,Andrew Philp

doi:10.1371/journal.pone.0156460

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.

Highlights

Skeletal muscle possesses a remarkable ability to regulate substrate use with changing substrate availability and energy demands [1,2]
The observations that the exercise bout in the present study was associated with a gradual decrease in respiratory exchange ratio (RER) and a transient increase in skeletal muscle PDHa activity in control mice as previously reported in humans [7,18,19]), suggest that the experimental setup provides the basis for studying the impact of muscle IL-6 on exercise-induced Pyruvate dehydrogenase (PDH) regulation in skeletal muscle and substrate utilization
It should be noted that this suggestion is possible PDHa activity was not significantly different between the genotypes at 2 h of exercise, because the plasma IL-6 levels were increased in both genotypes at 2 h of exercise

Summary

Introduction

Skeletal muscle possesses a remarkable ability to regulate substrate use with changing substrate availability and energy demands [1,2]. As the Randle cycle originally proposed [3], lipids and carbohydrates (CHO) play competitive but essential roles as substrate in energy production in muscle. The coordinated dynamic switch between these substrates is vital to sustaining ATP production during prolonged metabolic challenges such as exercise. The demand for energy supply increases many fold over resting state requirements at the onset of exercise and PLOS ONE | DOI:10.1371/journal.pone.0156460. Lack of Skeletal Muscle IL-6 Affects PDHa Activity at Rest and during Prolonged Exercise The demand for energy supply increases many fold over resting state requirements at the onset of exercise and PLOS ONE | DOI:10.1371/journal.pone.0156460 June 21, 2016

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