基于AMPK/PGC-1α通路的线粒体质量控制研究白藜芦醇改善高脂诱导的肌肉衰减的作用及其机制

The two greatest public health concerns in the world are the aging of the population and the obesity widespread. Aging is accompanied with a progressive loss of muscle mass and strength, called sarcopenia that affects dramatically health status and quality of life. Pharmacologic interventions have been unsatisfactory, and the core management strategies remain physical exercise and nutritional supplementation; however, further research is required to determine the most beneficial approaches. Obesity and excessive intake of saturated fatty acids appear to be the promoting factors to sarcopenia. Sarcopenia is a complex multifactorial process. Recently, mitochondrial dysfunction has been long suggested as one of the mechanisms of aging sarcopenia. Dysfunctional mitochondria trigger catabolic signaling pathways which feed-forward to the nucleus to promote the activation of muscle atrophy. Optimized mitochondrial function is strictly maintained by the coordinated activation of different mitochondrial quality control pathways. Up-regulation of AMPK/PGC-1α signaling pathway not only increase mitochondrial content but also mitochondrial quality by modulating fusion/fission processes and mitophagy to prevent muscle loss. Our previous study shown that resveratrol could attenuate vascular endothelial inflammation by improving mitochondrial function through the AMPK/PGC-1αsignaling pathway. We found that resveratrol could improve the muscle atrophy of obesity rats while we researched the protective effect of resveratrol on non-alcoholic fatty liver disease. Thus, we hypothesized that resveratrol might prevent the muscle atrophy inducing by saturated fatty acid through modulating the mitochondrial quality control via up-regulation of AMPK/PGC-1αsignaling pathway.To confirm this hypothesis, we would like to examine the effects of resveratrol at different doses and time intervals on muscle atrophy following palmitic acid stimulation in cultured L6 myotubes and in a rat model of sarcopenia, and the potential role of mitochondrial quality control in preventing muscle loss. Furthermore, the potential involvement of the AMPK/PGC-1α signaling pathway was also investigated. This study has important theoretical and application prospects for prevention of sarcopenia through dietary approaches.

人口老龄化和肥胖是全球面临的两大公共卫生问题，与增龄相关的肌肉衰减综合征严重影响老年人生活质量，且缺乏理想防治措施。肥胖或过量饱和脂肪酸促进肌肉衰减发生发展，且与骨骼肌线粒体质量控制异常密切相关，激活AMPK/PGC-1α通路可促进肌细胞线粒体合成、调节线粒体融合分裂和线粒体自噬而延缓肌肉衰减。项目组研究发现白藜芦醇可上调AMPK/PGC-1α通路改善血管内皮细胞线粒体功能，在研究白藜芦醇防治非酒精脂肪肝时发现肥胖大鼠腓肠肌萎缩，而白藜芦醇干预可有效改善，结合有关研究进展，提出“白藜芦醇通过AMPK/PGC-1α信号通路调节线粒体质量控制而改善高脂诱导的肌肉衰减”的科学假说。本项目用软脂酸处理L6肌管细胞建立肌萎缩细胞模型和高脂饲料喂养建立少肌性肥胖大鼠模型，围绕线粒体质量控制，探讨白藜芦醇通过AMPK/PGC-1α通路改善高脂诱导的肌肉衰减的作用及机制，为防治肌肉衰减综合征提供科学依据。

人口老龄化和肥胖是全球面临的两大公共卫生问题，与增龄相关的肌肉衰减综合征严重影响老年人生活质量，且缺乏理想防治措施。肥胖或过量饱和脂肪酸促进肌肉衰减发生发展，且与骨骼肌线粒体质量控制异常密切相关。项目组提出“白藜芦醇通过AMPK/PGC-1α信号通路调节线粒体质量控制而改善高脂诱导的肌肉衰减”的科学假说，并用软脂酸处理L6肌管细胞建立肌萎缩细胞模型和高脂饲料喂养建立少肌性肥胖大鼠模型，围绕线粒体质量控制，探讨白藜芦醇通过AMPK/PGC-1α通路改善高脂诱导的肌肉衰减的作用及机制。高脂喂养明显导致老年大鼠体脂含量增加，骨骼肌质量减少，肌纤维横截面积减小，抓力下降，提示老年大鼠肥胖性肌肉衰减症模型建立成功；RSV干预可抑制高脂诱导的老年大鼠脂肪蓄积以及肌肉质量和肌纤维横截面积的下降，并提升抓力，表明RSV能有效改善高脂诱导的肥胖性肌肉衰减症。PA导致L6肌管细胞中MHC蛋白水平和肌管直径显著降低；RSV处理可抑制PA诱导的MHC水平和肌管直径的减少，表明RSV能抑制PA诱导的肌细胞萎缩。我们的研究证实了线粒体功能紊乱、氧化应激和骨骼肌异位脂质沉积在肥胖性肌肉衰减症的发生发展中起重要作用。RSV可通过AMPK/PGC-1α通路减轻骨骼肌线粒体功能紊乱和氧化应激，以及通过PPARδ/CPT-1通路抑制骨骼肌的异位脂质沉积，进而改善高脂诱导的肥胖性肌肉衰减症。这些发现对阐明肥胖性肌肉衰减症的病理生理机制具有重要的理论意义，也为RSV对肥胖性肌肉衰减症的潜在防治作用提供了依据。