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

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.

The Acute Effects of 5 Fluorouracil on Skeletal Muscle Resident and Infiltrating Immune Cells in Mice

“…Surprisingly, while inflammation is a hallmark of cancer cachexia associated with muscle weakness and fatigue (VanderVeen et al, 2017(VanderVeen et al, , 2018, total macrophage number was reduced in damaged muscle of C26 tumor-bearing mice compared to a non-cachectic tumorbearing control (Inaba et al, 2018). Additionally, macrophages were shown to regulate skeletal muscle signal transducer and activator of transcription 3 (STAT3) -downstream target of IL-6 and key regulator of skeletal muscle mitochondrial homeostasis and proteostasis (Carson and Kristen, 2010;Bonetto et al, 2011Bonetto et al, , 2012VanderVeen et al, 2017VanderVeen et al, , 2019 -during pancreatic cancer cachexia (Shukla et al, 2020). Further work is needed to understand these potentially overlapping mechanisms with cancer and chemotherapy on skeletal muscle immune cells.…”

Increased high molecular weight adiponectin and lean mass during tocilizumab treatment in patients with rheumatoid arthritis: a 12-month multicentre study

“…How IL-6 inhibition may impact the lean/muscle mass is unknown, but probably results from anabolic effects on myocytes. Indeed, circulating IL-6 has established effects on skeletal muscle mass and metabolism [39]. IL-6, in conjunction with TNFα, may promote muscle loss and is associated with a decline in muscle mass and muscle strength, especially in older people.…”

Post-COVID-19 Fatigue: Potential Contributing Factors

“…COVID-19 in the lungs activates various leukocytes to release a cascade of cytokines, including interleukin-6 (IL-6) [ 35 ]. Notably, systemic elevations of IL-6 can disrupt muscle metabolic homeostasis and exacerbate muscle loss [ 36 ]. Thus, Ferrandi et al [ 34 ] postulate that skeletal muscle may be impacted by COVID-19 through direct infection of resident ACE2-rich cell types and/or indirectly through systemic cytokine release and subsequent homeostatic perturbation.…”