IL-6 Promotes Muscle Atrophy by Increasing Ubiquitin–Proteasome Degradation of Muscle Regeneration Factors After Cerebral Infarction in Rats

Muscle atrophy in pathological or diseased muscles arises from an imbalance between protein synthesis and degradation. Elevated levels of interleukin-6 (IL-6) are a hallmark of ischemic stroke and have been associated with muscle atrophy in certain pathological contexts. However, the mechanisms by which IL-6 induces muscle atrophy in the context of stroke remain unclear. To investigate these effects, we used a rat model of middle cerebral artery occlusion (MCAO) and an in vitro model with the C2C12 cell line to uncover potential molecular mechanisms underlying IL-6-induced muscle atrophy. Our findings revealed elevated protein and serum levels of IL-6, along with increased markers of muscle atrophy, in MCAO rats compared to sham controls. We also observed overactivation of protein ubiquitination pathways and downregulation of muscle regeneration markers in MCAO rats. Further analysis indicated that IL-6 contributes to increased muscle protein ubiquitination. Inhibition of IL-6 signaling led to a significant reduction in infarct size and improved neurological deficit scores. Targeting the IL-6/IL-6R signaling pathway presents a promising therapeutic approach to mitigate muscle atrophy in individuals affected by ischemic stroke.