HMB和利拉鲁肽对高糖加游离脂肪酸处理的C2C12肌管中的脂毒性和萎缩性改变提供互补保护作用
HMB and Liraglutide Confer Complementary Protection Against Lipotoxic and Atrophic Alterations in High-Glucose Plus Free Fatty Acid-Treated C2C12 Myotubes.
摘要(中文译文)
2型糖尿病（T2D）相关肌少症的特征是胰岛素信号受损、脂毒性、氧化应激和进行性肌肉丢失。尽管利拉鲁肽可改善血糖控制并减轻脂质负荷，但其在糖尿病脂毒性条件下维持肌肉完整性的能力仍然有限。本研究探讨了β-羟基-β-甲基丁酸（HMB）能否增强利拉鲁肽对高糖联合游离脂肪酸（HG+FFA）诱导的骨骼肌细胞损伤的保护作用。将分化的C2C12肌管暴露于HG+FFA以建立亚致死性脂毒性模型，并给予利拉鲁肽、HMB或其联合处理。评估了细胞活力、脂质蓄积、肌管形态、胰岛素信号、葡萄糖摄取、线粒体功能、活性氧（ROS）、抗氧化基因表达及萎缩相关信号。HG+FFA诱导了明显的脂滴蓄积、胰岛素信号受损、葡萄糖摄取减少、线粒体膜电位破坏、ROS产生增加、抗氧化基因表达受抑，并促进以atrogin-1和MuRF1升高及肌源性标志物降低为特征的萎缩表型。单用利拉鲁肽可减少大脂滴并部分改善胰岛素信号，但在维持肌管表型方面疗效有限。单用HMB对脂质蓄积影响 modest，但可保留肌管面积。值得注意的是，HMB与利拉鲁肽联合处理更有效地减轻脂质负荷、恢复胰岛素信号和葡萄糖摄取、减轻线粒体功能障碍和氧化应激、恢复抗氧化基因表达，并保留MyHC阳性面积和肌管直径，同时抑制atrogin-1/MuRF1活化。这些保护作用在很大程度上被雷帕霉素削弱，表明至少部分依赖于mTOR相关信号。总体而言，HMB与利拉鲁肽对糖尿病脂毒性和萎缩应激发挥互补性保护作用，支持该联合策略用于T2D相关肌少症的潜在价值。
Abstract
Type 2 diabetes (T2D)-associated sarcopenia is characterized by impaired insulin signaling, lipotoxicity, oxidative stress, and progressive muscle loss. Although liraglutide improves glucose control and reduces lipid burden, its ability to preserve muscle integrity under diabetic lipotoxic conditions remains limited. This study investigated whether β-hydroxy-β-methylbutyrate (HMB) could enhance liraglutide-mediated protection against high-glucose plus free fatty acid (HG+FFA)-induced injury in skeletal muscle cells. Differentiated C2C12 myotubes were exposed to HG+FFA to establish a sublethal lipotoxic model and treated with liraglutide, HMB, or their combination. Cell viability, lipid accumulation, myotube morphology, insulin signaling, glucose uptake, mitochondrial function, reactive oxygen species (ROS), antioxidant gene expression, and atrophy-related signaling were assessed. HG+FFA induced marked lipid droplet accumulation, impaired insulin signaling, reduced glucose uptake, disrupted mitochondrial membrane potential, increased ROS production, suppressed antioxidant gene expression, and promoted an atrophic phenotype characterized by increased atrogin-1 and MuRF1 and reduced myogenic markers. Liraglutide alone reduced large lipid droplets and partially improved insulin signaling but showed limited efficacy in preserving the myotube phenotype. HMB alone exerted modest effects on lipid accumulation but preserved myotube area. Notably, combined HMB and liraglutide treatment more effectively reduced lipid burden, restored insulin signaling and glucose uptake, attenuated mitochondrial dysfunction and oxidative stress, restored antioxidant gene expression, and preserved MyHC-positive area and myotube diameter while suppressing atrogin-1/MuRF1 activation. These protective effects were largely attenuated by rapamycin, indicating at least partial dependence on mTOR-associated signaling. Overall, HMB and liraglutide exert complementary protective effects against diabetic lipotoxic and atrophic stress, supporting the potential utility of this combination strategy for T2D-associated sarcopenia.
如何引用
AMA
Li-Yuan Chen, Shao-Hsing Weng, Hsin-Hua Li, Chen-Hsing Su, Sing-Hua Tsou, Kuei-Chuan Chan, et al. HMB and Liraglutide Confer Complementary Protection Against Lipotoxic and Atrophic Alterations in High-Glucose Plus Free Fatty Acid-Treated C2C12 Myotubes.. Nutrients. 2026; doi:10.3390/nu18121865.
APA
Li-Yuan Chen, Shao-Hsing Weng, Hsin-Hua Li, Chen-Hsing Su, Sing-Hua Tsou, Kuei-Chuan Chan, et al (2026). HMB and Liraglutide Confer Complementary Protection Against Lipotoxic and Atrophic Alterations in High-Glucose Plus Free Fatty Acid-Treated C2C12 Myotubes.. Nutrients. https://doi.org/10.3390/nu18121865
GB/T 7714
Li-Yuan Chen, Shao-Hsing Weng, Hsin-Hua Li, Chen-Hsing Su, Sing-Hua Tsou, Kuei-Chuan Chan, et al. HMB and Liraglutide Confer Complementary Protection Against Lipotoxic and Atrophic Alterations in High-Glucose Plus Free Fatty Acid-Treated C2C12 Myotubes.[J]. Nutrients, 2026 doi:10.3390/nu18121865.
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