Bae Sanghoon, Mai Van-Hieu, Mun Seyoung, Dong Dalong, Han Kyudong, Park Sunghyouk, Hyun Jung Keun
Department of Nanobiomedical Science & BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Korea.
Natural Product Research Institute, College of Pharmacy, Seoul National University, Seoul, Korea.
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1):e13665. doi: 10.1002/jcsm.13665. Epub 2024 Dec 17.
Muscle atrophy, including glucocorticoid-induced muscle wasting from treatments such as dexamethasone (DEX), results in significant reductions in muscle mass, strength and function. This study investigates the potential of lonafarnib, a farnesyltransferase inhibitor, to counteract DEX-induced muscle atrophy by targeting key signalling pathways.
We utilized in vitro models with C2C12 myotubes treated with DEX and in vivo models with Caenorhabditis elegans and DEX-treated Sprague-Dawley rats. Myotube morphology was assessed by measuring area, fusion index and diameter. Muscle function was evaluated by grip strength and compound muscle action potential (CMAP) in the gastrocnemius (GC) and tibialis anterior (TA) muscles. Molecular mechanisms were explored through RNA sequencing and Western blotting to assess changes in mitochondrial function and muscle signalling pathways.
Lonafarnib (2 μM) significantly improved myotube area (1.49 ± 0.14 × 10 μm vs. 1.03 ± 0.49 × 10 μm in DEX, p < 0.05), fusion index (18.73 ± 1.23% vs. 13.3 ± 1.56% in DEX, p < 0.05) and myotube diameter (31.89 ± 0.89 μm vs. 21.56 ± 1.01 μm in DEX, p < 0.05) in C2C12 myotubes. In C. elegans, lonafarnib (100 μM) increased the pharyngeal pumping rate from 212 ± 7.21 contractions/min in controls to 308 ± 17.09 contractions/min at day 4 (p < 0.05), indicating enhanced neuromuscular function. In DEX-induced atrophic rats, lonafarnib improved maximal grip strength (DEX: 13.91 ± 0.78 N vs. 1 μM lonafarnib: 16.18 ± 0.84 N and 5 μM lonafarnib: 16.71 ± 0.83 N, p < 0.05), increased muscle weight in GC, and enhanced CMAP amplitudes in both GC and TA muscles. Western blot analysis showed that lonafarnib treatment upregulated UCP3 and ANGPTL4 and increased phosphorylation of mTOR and S6 ribosomal protein (p < 0.05), indicating enhanced mitochondrial function and protein synthesis. Knockdown models further demonstrated that lonafarnib could partially rescue muscle atrophy phenotypes, indicating its action through multiple molecular pathways.
Lonafarnib mitigates dexamethasone-induced muscle atrophy by enhancing mitochondrial function and activating anabolic pathways. These findings support further investigation of lonafarnib as a therapeutic agent for muscle atrophy in clinical settings.
肌肉萎缩，包括地塞米松（DEX）等治疗引起的糖皮质激素诱导的肌肉消耗，会导致肌肉质量、力量和功能显著下降。本研究调查法尼基转移酶抑制剂洛那法尼通过靶向关键信号通路来对抗DEX诱导的肌肉萎缩的潜力。
我们利用体外模型，用DEX处理C2C12肌管，以及体内模型，用秀丽隐杆线虫和DEX处理的Sprague-Dawley大鼠。通过测量面积、融合指数和直径来评估肌管形态。通过握力以及腓肠肌（GC）和胫前肌（TA）的复合肌肉动作电位（CMAP）来评估肌肉功能。通过RNA测序和蛋白质印迹法探索分子机制，以评估线粒体功能和肌肉信号通路的变化。
洛那法尼（2 μM）显著改善了C2C12肌管的肌管面积（1.49±0.14×10μm，而DEX组为1.03±0.49×10μm，p< 0.05）、融合指数（18.73±1.23%，而DEX组为13.3±1.56%，p< 0.05）和肌管直径（31.89±0.89μm，而DEX组为21.56±1.01μm，p< 0.05）。在秀丽隐杆线虫中，洛那法尼（100 μM）将咽部抽吸率从对照组的212±7.21次收缩/分钟提高到第4天的308±17.09次收缩/分钟（p< 0.05），表明神经肌肉功能增强。在DEX诱导的萎缩大鼠中，洛那法尼改善了最大握力（DEX组：13.91±0.78 N，而1 μM洛那法尼组：16.18±0.84 N，5 μM洛那法尼组：16.71±0.83 N，p< 0.05），增加了GC的肌肉重量，并增强了GC和TA肌肉的CMAP幅度。蛋白质印迹分析表明，洛那法尼治疗上调了UCP3和ANGPTL4，并增加了mTOR和S6核糖体蛋白的磷酸化（p< 0.05），表明线粒体功能和蛋白质合成增强。基因敲低模型进一步证明，洛那法尼可以部分挽救肌肉萎缩表型，表示其通过多种分子途径发挥作用。
洛那法尼通过增强线粒体功能和激活合成代谢途径减轻地塞米松诱导的肌肉萎缩。这些发现支持进一步研究洛那法尼作为临床环境中肌肉萎缩治疗药物的可能性。
