肠道P.merdae菌调控骨骼肌细胞AMPK通路在老年性肌少症进展中的机制研究

老年性肌少症患病率高、危害大，但因其受关注程度低且机制未明，该病的防治一直困扰临床医师。申请人前期研究发现，老年性肌少症患者肠道菌群紊乱，尤其肠道产短链脂肪酸菌P.merdae特异性减少；并且该菌的减少不仅与疾病进展和不良预后相关，也与宿主AMPK通路的下调相关；此外，AMPK通路下调可破坏骨骼肌线粒体的稳态进而诱导能量应激的发生。据此推测，老年性肌少症患者肠道P.merdae菌的降低可能通过失调的代谢产物下调骨骼肌AMPK信号通路，从而影响骨骼肌的能量稳态和功能，进而引起疾病的发生发展。本项目拟以老年性肌少症患者、无菌小鼠及骨骼肌细胞为研究模型，以肠道菌群为研究对象，聚焦于骨骼肌AMPK通路异常引起的能量稳态失衡，阐明P.merdae菌及其代谢产物在老年性肌少症中的作用机制，探索粪菌移植和运动疗法通过调节肠道菌群作为肌少症的治疗手段的可行性，为该病机制的阐释和防治方法的开发提供新思路。

Sarcopenia is a significant public health problem and carries with substantial disability and mortality. However, sarcopenia does not get enough attention and the mechanism of it has not yet been clarified, the prevention and treatment of sarcopenia is a major problem that plagues clinicians. In our previous study, we have identified that the α- and β-diversity of gut microbiota in patients with sarcopenia was decreased. More importantly, the short-chain fatty acid bacteria specifically P.merdae decreased in the gut microbiota of patients with sarcopenia. Moreover, the reduction of P.merdae bacteria is not only related to disease progression and poor prognosis, but also to the down-regulation of AMPK pathway in skeletal muscle. In addition, down-regulation of AMPK pathway can disrupt the homeostasis of skeletal muscle mitochondria and the induction of energy stress. Therefore, we hypothesize that the damage of intestinal flora in patients with sarcopenia, especially the reduction of P.merdae bacteria, may downregulate the AMPK signal pathway of skeletal muscle through dysregulated metabolites, thereby affecting the energy homeostasis and function of skeletal muscle and aggravating the progression of sarcopenia. This project intends to use sarcopenia patients, germ-free mice and skeletal muscle cells as research models focusing on the energy homeostasis caused by skeletal muscle AMPK pathway abnormalities, and verifying the role of P.merdae bacteria and its metabolites in the occurrence and development of sarcoma. In this study, we will also explore the feasibility of fecal bacterial transplantation and exercise therapy by adjusting the intestinal flora as a treatment method for sarcopenia. The study will not only enrich the understanding of the pathogenesis of sarcopenia, but also provide new methods for its early diagnosis and prognosis prediction.