Abstract：
Sarcopenia is a significant geriatric syndrome that involves the loss of skeletal muscle mass and strength. Due to its substantial endocrine role, the metabolic microenvironment of skeletal muscle undergoes changes with age. Examining the pathogenesis of sarcopenia through focusing on metabolic dysregulation could offer insights for developing more effective intervention strategies. In this study, we analyzed the transcriptomics data to identify specific genes involved in the regulation of metabolism in skeletal muscle during the development of sarcopenia. Three machine learning algorithms were employed to screen key target genes exhibiting strong correlations with metabolism, which were further validated using RNA-sequencing data and publicly accessible datasets. Among them, the metabolic enzyme nicotinamide N-methyltransferase (NNMT) was elevated in sarcopenia, and predicted sarcopenia with an area under the curve exceeding 0.7, suggesting it as a potential therapeutic target for sarcopenia. As expected, inhibition of NNMT improved the grip strength in aging mice and alleviated age-related decline in the mass index of the quadriceps femoris muscles and whole-body lean mass index. Additionally, the NNMTi treatment increased the levels of nicotinamide adenine dinucleotide (NAD+) content, as well as PGC1α and p-AMPK expression in the muscles of both the D-galactose-treated mouse model and naturally aging mouse model. Overall, this work demonstrates NNMT as a promising target for preventing age-related decline in muscle mass and strength.
摘要：
肌肉减少症是一种重要的老年综合征，涉及骨骼肌质量和力量的丧失。由于其实质性的内分泌作用，骨骼肌的代谢微环境随着年龄的增长而变化。通过关注代谢失调来检查肌肉减少症的发病机理可以为制定更有效的干预策略提供见解。在这项研究中,我们分析了转录组学数据，以确定在肌肉减少症发展过程中参与骨骼肌代谢调节的特定基因。采用三种机器学习算法筛选与代谢密切相关的关键靶基因，使用RNA测序数据和可公开访问的数据集进一步验证。其中,代谢酶烟酰胺N-甲基转移酶（NNMT）在肌肉减少症中升高，并预测肌肉减少症的曲线下面积超过0.7，表明它是肌肉减少症的潜在治疗靶点。不出所料,抑制NNMT可改善衰老小鼠的握力，并减轻与年龄相关的股四头肌质量指数和全身瘦体重指数的下降。此外,NNMTi治疗增加了烟酰胺腺嘌呤二核苷酸（NAD+）的含量，以及D-半乳糖处理的小鼠模型和自然衰老小鼠模型的肌肉中的PGC1α和p-AMPK表达。总的来说,这项工作证明NNMT是预防与年龄相关的肌肉质量和力量下降的有希望的目标.
