The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated IL‐6

New Findings

What is the central question of this study?

Interleukin‐6 has been associated with muscle mass and metabolism with both physiological and pathological conditions. A causal role for IL‐6 to induce fatigue and disrupt mitochondrial function has not been determined.

What is the main finding and its importance?

We demonstrate that chronically elevated IL‐6 increased skeletal muscle fatigability and disrupted mitochondrial content and function independent of fiber‐type and mass changes.

Abstract

Background

Interleukin‐6 (IL‐6) can initiate intracellular signaling in skeletal muscle through binding to the IL‐6‐receptor and interaction 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 if chronically elevated systemic IL‐6 was sufficient to disrupt skeletal muscle force, fatigue, and mitochondrial function. Additionally, we examined the role of muscle gp130 signaling during IL‐6 over‐expression.

Methods

Systemic IL‐6 overexpression for 2‐weeks was achieved by electroporation of an IL‐6 over‐expression 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.

Results

IL‐6 accelerated in situ skeletal muscle fatigue in the WT; a 18.5% reduction in force within 90s of repeated submaximal contractions and a 7% reduction in maximal tetanic force following 5 minutes. There was no difference between KO and KO+IL‐6 fatigue. IL‐6 reduced WT muscle mitochondrial respiratory control ratio (RCR) 36% and COX activity 42%. IL‐6 had no effect on either KO RCR or COX activity. IL‐6 also had no effect on body weight, muscle mass, or tetanic force in either genotype.

Conclusions

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 signaling.

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