Extramyocellular interleukin-6 influences skeletal muscle mitochondrial physiology through canonical JAK/STAT signaling pathways

• Published in: The FASEB journal Vol. 34; no. 11; p. 14458
• Main Authors: Abid, Hinnah, Ryan, Zachary C, Delmotte, Philippe, Sieck, Gary C, Lanza, Ian R
• Format: Journal Article
• Language: English
• Published: United States 01.11.2020
• Subjects: Animals; Antioxidants - pharmacology; Cell Line; Interleukin-6 - pharmacology; Janus Kinases - metabolism; Mice; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - metabolism; Muscle Fibers, Skeletal - metabolism; Organophosphorus Compounds - pharmacology; Reactive Oxygen Species - metabolism; Signal Transduction; STAT3 Transcription Factor - metabolism; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology; skeletal muscle; mitochondria; interleukin-6; STAT3; reactive oxygen species
• ISSN: 1530-6860
• DOI: 10.1096/fj.202000965RR

Interleukin-6 (IL-6) is a pleiotropic cytokine that has been shown to be produced acutely by skeletal muscle in response to exercise, yet chronically elevated with obesity and aging. The mechanisms by which IL-6 influences skeletal muscle mitochondria acutely and chronically are unclear. To better understand the influence of extramyocellular IL-6 on skeletal muscle mitochondrial physiology, we treated differentiated myotubes with exogenous IL-6 to evaluate the dose- and duration-dependent effects of IL-6 on salient aspects of mitochondrial biology and the role of canonical IL-6 signaling in muscle cells. Acute exposure of myotubes to IL-6 increased the mitochondrial reactive oxygen species (mtROS) production and oxygen consumption rates (JO ) in a manner that was dependent on activation of the JAK/STAT pathway. Furthermore, STAT3 activation by IL-6 was partly attenuated by MitoQ, a mitochondrial-targeted antioxidant, suggesting that mtROS potentiates STAT3 signaling in skeletal muscle in response to IL-6 exposure. In concert with effects on mitochondrial physiology, acute IL-6 exposure induced several mitochondrial adaptations, consistent with the stress-induced mitochondrial hyperfusion. Exposure of myotubes to chronically elevated IL-6 further increased mtROS with eventual loss of respiratory capacity. These data provide new evidence supporting the interplay between cytokine signaling and mitochondrial physiology in skeletal muscle.