Choi Ran Hee, Karasawa Takuya, Meza Cesar A, Maschek J Alan, Manuel Allison, Nikolova Linda S, Fisher-Wellmen Kelsey H, Cox James E, Chaix Amandine, Funai Katsuhiko
Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, UT, USA.
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.
bioRxiv. 2024 Nov 15:2024.11.13.623431. doi: 10.1101/2024.11.13.623431.
Glucagon-like peptide 1 receptor agonists (e.g. semaglutide) potently induce weight loss and thereby reducing obesity-related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet-mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency.
C57BL/6J mice were fed a high-fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rate of ATP production and O consumption were measured by a high-resolution respirometry and fluorometry to determine OXPHOS efficiency in skeletal muscle at these 2 timepoints.
Semaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O consumed (P/O) in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (Lyrm7 and Ttc1, p <0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits.
These data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.
胰高血糖素样肽1受体激动剂（如司美格鲁肽）能有效诱导体重减轻，从而减少肥胖相关并发症。然而，停药后体重会反弹。饮食介导的体重减轻后骨骼肌氧化磷酸化（OXPHOS）效率增加，这可能导致全身能量消耗减少和体重反弹。我们着手确定司美格鲁肽对肌肉OXPHOS效率的未知影响。
C57BL/6J小鼠先高脂饮食12周，然后接受司美格鲁肽或赋形剂治疗1周或3周。通过高分辨率呼吸测定法和荧光测定法测量ATP生成率和耗氧量，以确定这两个时间点骨骼肌中的OXPHOS效率。
司美格鲁肽治疗导致脂肪和瘦体重显著减少。司美格鲁肽提高了骨骼肌的OXPHOS效率，以通透肌纤维中每消耗一个O2产生的ATP（P/O）来衡量。线粒体蛋白质组学分析显示，变化仅限于与复合物III组装相关的两种蛋白质（Lyrm7和Ttc1，未经多重校正时p<0.05），而OXPHOS亚基的丰度没有实质性变化。
这些数据表明，司美格鲁肽治疗引起的体重减轻增加了骨骼肌线粒体效率。未来的研究可以测试它是否会导致体重反弹。
