Dalle Sebastiaan, Schouten Moniek, Vanderbeke Kaat, Van Parys Evy, Ramaekers Monique, Thomis Martine, Costamagna Domiziana, Koppo Katrien
Exercise Physiology Research Group, Department of Movement Sciences, KU Leuven, Tervuursevest 101, 3001 Leuven, Belgium; MOVANT Research Group, Department of Rehabilitation Sciences and Physiotherapy, University of Antwerp, Antwerp, Belgium.
Exercise Physiology Research Group, Department of Movement Sciences, KU Leuven, Tervuursevest 101, 3001 Leuven, Belgium.
Life Sci. 2025 Jan 15;361:123296. doi: 10.1016/j.lfs.2024.123296. Epub 2024 Dec 5.
Skeletal muscle regeneration upon injury requires timely activation of inflammatory, myogenic, fibrotic, apoptotic and anabolic systems. Optimization of these features might improve the recovery process. Whereas recent data indicate that the endocannabinoid system, and more particularly cannabinoid receptor 1 (CB1) antagonism, is involved in the regulation of inflammatory, myogenic, fibrotic, apoptotic and anabolic pathways, it was never studied whether CB1 antagonism can improve muscle regeneration. The present study investigated the effect of the CB1 antagonist Rimonabant (10 mg/kg/d) on functional (5 days post-cardiotoxin injury; 5DPI) and molecular muscle responses (3DPI and 7DPI) in mice. Rimonabant prevented cardiotoxin-induced muscle strength loss 5DPI, increased myofiber growth (7DPI) and improved the muscle molecular profile 3DPI and 7DPI. In general, inflammation (e.g. p-p65NF-κB, CD80) and apoptosis (e.g. cleaved caspase-3, cleaved PARP) were downregulated by Rimonabant, whereas it upregulated the expression of Pax7 but other myogenic factors remained unaffected by rimonabant. In addition, Rimonabant restored the injury-induced (inflammatory) lipid profile to a large extent, including oxygenated fatty acids, unsaturated fatty acids and endocannabinoids such as 2-arachidonoyl glycerol and palmitoylethanolamide. Altogether, these data show that the endocannabinoid system might be a novel therapeutic target to improve muscle regeneration, which is relevant for age- and disease-related muscle degeneration.
损伤后骨骼肌的再生需要及时激活炎症、生肌、纤维化、凋亡和合成代谢系统。优化这些特性可能会改善恢复过程。尽管最近的数据表明内源性大麻素系统，尤其是大麻素受体1（CB1）拮抗剂，参与了炎症、生肌、纤维化、凋亡和合成代谢途径的调节，但从未研究过CB1拮抗剂是否能改善肌肉再生。本研究调查了CB1拮抗剂利莫那班（10毫克/千克/天）对小鼠功能性（心肌毒素损伤后5天；5DPI）和分子肌肉反应（3DPI和7DPI）的影响。利莫那班可预防心肌毒素诱导的5DPI时肌肉力量丧失，增加肌纤维生长（7DPI），并改善3DPI和7DPI时的肌肉分子特征。一般来说，利莫那班可下调炎症（如p-p65NF-κB、CD80）和凋亡（如裂解的半胱天冬酶-3、裂解的PARP），而上调Pax7的表达，但其他生肌因子不受利莫那班影响。此外，利莫那班在很大程度上恢复了损伤诱导的（炎症性）脂质谱，包括氧化脂肪酸、不饱和脂肪酸和内源性大麻素，如2-花生四烯酰甘油和棕榈酰乙醇胺。总之，这些数据表明内源性大麻素系统可能是改善肌肉再生的一个新的治疗靶点，这与年龄和疾病相关的肌肉退化有关。
