Department of General Practice, The First Affiliated Hospital of Chongqing Medical University, No.1 Yi Xue Yuan Road, Yuzhong District, Chongqing 400016, China.
Department of Physiology and Pharmacology, Karolinska Institutet, Bioclinicum, J8:30, SE-171 77 Stockholm, Sweden.
Biochim Biophys Acta Mol Basis Dis. 2022 Nov 1;1868(11):166508. doi: 10.1016/j.bbadis.2022.166508. Epub 2022 Jul 26.
Sarcopenia and obese sarcopenia are increasingly prevalent chronic diseases with multifactorial pathogenesis, and no approved therapeutic drug to date. In the established sarcopenic mice models, muscle weakness, ectopic lipid deposition, and inflammatory responses in both serum and gastrocnemius muscle were observed, which were even deteriorated in obese sarcopenic models. With metformin intervention for 5 months, metformin exhibited benefits and restoring effects on gastrocnemius muscle of sarcopenic mice, but less effective on that of obese sarcopenic mice, as reflected in the increased percentage of muscle mass and enlarged fiber cross-sectional area, enhanced grip strength and exercise capacities, as well as the ameliorated ectopic lipid deposition and partially restored level of TNF-α, IL-1β, IL-6, MCP-1 and IL-1α, which may be via the activation of phospho-AMPKα (Thr172). The significant up-regulated mRNA and protein level of lipolysis related proteins like hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) may contribute to the ameliorated ectopic lipid deposition with metformin intervention. The uptake of free fatty acid may be also inhibited in obese sarcopenic mice with metformin administration, as reflected in down-regulated mRNA and protein level of fatty acid transporter CD36. Furthermore, NF-κB signaling pathway was involved in the anti-inflammatory effect of metformin. These findings suggest that metformin treatment may be conducive to the prevention of age-related sarcopenia by regulating lipid metabolism in skeletal muscle, i.e. enhanced lipolysis and attenuated hyper-inflammatory responses, which may be AMPK-dependent processes. Moreover, high-fat diet would aggravate the damage to ageing in skeletal muscles and reduced their reactivity to metformin.
肌肉减少症和肥胖型肌肉减少症是两种日益流行的慢性疾病，具有多因素发病机制，目前尚无批准的治疗药物。在已建立的肌肉减少症小鼠模型中，观察到肌肉无力、异位脂质沉积和血清及比目鱼肌中的炎症反应，在肥胖型肌肉减少症模型中甚至更为恶化。用二甲双胍干预 5 个月后，二甲双胍对肌肉减少症小鼠的比目鱼肌表现出益处和恢复作用，但对肥胖型肌肉减少症小鼠的效果较差，表现为肌肉质量百分比增加和纤维横截面积增大、握力和运动能力增强、异位脂质沉积改善以及 TNF-α、IL-1β、IL-6、MCP-1 和 IL-1α水平部分恢复，这可能是通过磷酸化 AMPKα（Thr172）的激活。脂解相关蛋白如激素敏感脂肪酶（HSL）和脂肪甘油三酯脂肪酶（ATGL）的 mRNA 和蛋白水平显著上调，可能有助于二甲双胍干预改善异位脂质沉积。二甲双胍给药还可能抑制肥胖型肌肉减少症小鼠的游离脂肪酸摄取，反映在脂肪酸转运蛋白 CD36 的 mRNA 和蛋白水平下调。此外，NF-κB 信号通路参与了二甲双胍的抗炎作用。这些发现表明，二甲双胍治疗可能通过调节骨骼肌中的脂质代谢，即增强脂解和减弱过度炎症反应，从而有利于预防与年龄相关的肌肉减少症，这可能是 AMPK 依赖性过程。此外，高脂肪饮食会加重衰老对骨骼肌的损害，并降低其对二甲双胍的反应性。
