β3‑adrenergic receptor agonist improves recovery after volumetric muscle loss and is associated with increased intramuscular brown/beige adipogenic activity in mice

Abstract Background Volumetric muscle loss (VML) often results in chronic muscle weakness, limb dysfunction, and even permanent disability. Current research primarily focuses on cell and extracellular matrix transplantation, but there is a lack of studies on the physiologically supportive intervention to enhance endogenous muscle recovery after VML. Recent studies have shown that β3-adrenergic receptor (β3AR) agonists can increase intramuscular UCP-1 expression and the proportion of PDGFRα-GFP/UCP-1 double-positive cells, a process associated with muscle recovery. This study aims to elucidate the role of the β3AR agonist Amibegron in promoting intramuscular brown/beige-like adipogenic activity to improve muscle atrophy, fibrosis and limb function after VML injury in mice. Methods Three-month-old PDGFRα-GFP reporter mice and C57BL/6J mice were used in this study. A VML injury model was created in the tibialis anterior (TA) muscle using a biopsy punch. To induce fibro/adipogenic progenitors (FAPs) to differentiate into beige-like adipocytes, the β3AR agonist Amibegron was administered via intraperitoneal injection. Limb function was assessed by gait analysis at 2 and 6 weeks post-VML, and muscle histomorphological examination and RT-qPCR for muscle gene expression analysis were performed at the corresponding time points. Results Compared with the vehicle control group, histology and gait analysis showed that Amibegron administration for 2 and 6 weeks increased intramuscular brown/beige adipogenic activity and modestly improved VML-injured muscle mass, fibrosis, and limb function. Moreover, at 6 weeks of Amibegron administration, limb function showed a significant positive association with uncoupling protein-1 (UCP-1) expression. Conclusions β3AR agonist Amibegron attenuates VML-induced muscle atrophy and fibrosis and improves limb motor function. These improvements are associated with increased brown/beige activity, but the causal role of FAP-derived BAT is not yet established. Given systemic administration, benefits likely involve both local and systemic β3AR effects. This study provides a potential therapeutic strategy for VML.