The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin-6

Brandon N. VanderVeen, Dennis K. Fix, Ryan N. Montalvo, Brittany R. Counts, Ashley J. Smuder, E. Angela Murphy, Ho jin Koh, James Carson

Research output: Contribution to journalArticle

Abstract

New Findings: What is the central question of this study? Interleukin-6 has been associated with muscle mass and metabolism in both physiological and pathological conditions. A causal role for interleukin-6 in the induction of fatigue and disruption of mitochondrial function has not been determined. What is the main finding and its importance? We demonstrate that chronically elevated interleukin-6 increased skeletal muscle fatigability and disrupted mitochondrial content and function independent of changes in fibre type and mass. Abstract: Interleukin-6 (IL-6) can initiate intracellular signalling in skeletal muscle by binding to the IL-6-receptor and interacting with the transmembrane gp130 protein. Circulating IL-6 has established effects on skeletal muscle mass and metabolism in both physiological and pathological conditions. However, the effects of circulating IL-6 on skeletal muscle function are not well understood. The purpose of this study was to determine whether chronically elevated systemic IL-6 was sufficient to disrupt skeletal muscle force, fatigue and mitochondrial function. Additionally, we examined the role of muscle gp130 signalling during overexpression of IL-6. Systemic IL-6 overexpression for 2 weeks was achieved by electroporation of an IL-6 overexpression plasmid or empty vector into the quadriceps of either C57BL/6 (WT) or skeletal muscle gp130 knockout (KO) male mice. Tibialis anterior muscle in situ functional properties and mitochondrial respiration were determined. Interleukin-6 accelerated in situ skeletal muscle fatigue in the WT, with a 18.5% reduction in force within 90 s of repeated submaximal contractions and a 7% reduction in maximal tetanic force after 5 min. There was no difference between fatigue in the KO and KO+IL-6. Interleukin-6 reduced WT muscle mitochondrial respiratory control ratio by 36% and cytochrome c oxidase activity by 42%. Interleukin-6 had no effect on either KO respiratory control ratio or cytochrome c oxidase activity. Interleukin-6 also had no effect on body weight, muscle mass or tetanic force in either genotype. These results provide evidence that 2 weeks of elevated systemic IL-6 is sufficient to increase skeletal muscle fatigability and decrease muscle mitochondrial content and function, and these effects require muscle gp130 signalling.

Original languageEnglish (US)
Pages (from-to)385-397
Number of pages13
JournalExperimental Physiology
Volume104
Issue number3
DOIs
StatePublished - Mar 1 2019

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Interleukin-6
Skeletal Muscle
Muscles
Muscle Fatigue
Fatigue
Oxidoreductases
Interleukin-6 Receptors
Respiratory Muscles
Electroporation
Knockout Mice
Respiration
Plasmids
Genotype
Body Weight

All Science Journal Classification (ASJC) codes

  • Physiology

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The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin-6. / VanderVeen, Brandon N.; Fix, Dennis K.; Montalvo, Ryan N.; Counts, Brittany R.; Smuder, Ashley J.; Murphy, E. Angela; Koh, Ho jin; Carson, James.

In: Experimental Physiology, Vol. 104, No. 3, 01.03.2019, p. 385-397.

Research output: Contribution to journalArticle

VanderVeen, BN, Fix, DK, Montalvo, RN, Counts, BR, Smuder, AJ, Murphy, EA, Koh, HJ & Carson, J 2019, 'The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin-6', Experimental Physiology, vol. 104, no. 3, pp. 385-397. https://doi.org/10.1113/EP087429
VanderVeen, Brandon N. ; Fix, Dennis K. ; Montalvo, Ryan N. ; Counts, Brittany R. ; Smuder, Ashley J. ; Murphy, E. Angela ; Koh, Ho jin ; Carson, James. / The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin-6. In: Experimental Physiology. 2019 ; Vol. 104, No. 3. pp. 385-397.
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