Intrinsic IL-6 expression reduces rhIL-6-induced JAK/STAT activation and promotes glucose and oleic acid oxidation in cultured human myoblasts

Srpcic, A.; Mis, K.; Zvar Baskovic Gantar, B.; Dolinar, K.; Nygaard Mjaaseth, U.; Rustan, A. C.; Tranheim Kase, E.; Lakota, K.; Perdan Pirkmajer, K.; Pirkmajer, S.

doi:10.64898/2026.05.06.722928

bioRxiv · 10.64898/2026.05.06.722928

Intrinsic IL-6 expression reduces rhIL-6-induced JAK/STAT activation and promotes glucose and oleic acid oxidation in cultured human myoblasts

Srpcic, A.·Mis, K.·Zvar Baskovic Gantar, B.·Dolinar, K.·Nygaard Mjaaseth, U.·Rustan, A. C.·Tranheim Kase, E.·Lakota, K.·Perdan Pirkmajer, K.·Pirkmajer, S.

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Abstract

Interleukin-6 (IL-6), produced by skeletal muscle and extramuscular tissues, regulates skeletal muscle function through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. However, the interaction between intrinsic (locally produced) IL-6 and extrinsic (circulating) IL-6 in skeletal muscle remains unclear. We investigated whether and how intrinsic expression of IL-6 in cultured primary human myoblasts influences their response to extrinsic stimulation with recombinant human IL-6 (rhIL-6). Using gene silencing, we found that suppression of intrinsic IL-6 enhanced rhIL-6-induced phosphorylation of STAT1 and STAT3. Silencing STAT3 also increased rhIL-6-induced STAT1 phosphorylation, but silencing STAT1 had no effect on STAT3 phosphorylation. Pretreatment of myoblasts with neutralising anti-IL-6 antibodies increased phosphorylation of STAT1 and STAT3 induced by 50 ng/mL rhIL-6, whereas pretreatment with 5 ng/mL rhIL-6 reduced this response. Despite increased JAK/STAT signalling, IL-6 silencing decreased glucose and oleic acid uptake and oxidation under both basal and rhIL-6-stimulated conditions. Collectively, our results imply that intrinsic IL-6 restrains activation of the JAK/STAT pathway by extrinsic IL-6, but acts synergistically with it to promote myoblast energy metabolism.

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Srpcic, A., Mis, K., Zvar Baskovic Gantar, B., Dolinar, K., Nygaard Mjaaseth, U., Rustan, A. C., Tranheim Kase, E., Lakota, K., Perdan Pirkmajer, K., Pirkmajer, S.. 2026-05-07. Intrinsic IL-6 expression reduces rhIL-6-induced JAK/STAT activation and promotes glucose and oleic acid oxidation in cultured human myoblasts. https://doi.org/10.64898/2026.05.06.722928

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