确定烟酰胺 N-甲基转移酶是治疗肌肉疏松症的有希望的靶点。

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Aging Cell Pub Date : 2024-06-05 DOI:10.1111/acel.14236
Rui Liang, Qiao Xiang, Miao Dai, Taiping Lin, Dongmei Xie, Quhong Song, Yu Liu, Jirong Yue
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摘要

"肌肉疏松症 "是一种严重的老年综合症,表现为骨骼肌质量和力量的下降。由于骨骼肌具有重要的内分泌作用,其代谢微环境会随着年龄的增长而发生变化。通过关注代谢失调来研究肌肉疏松症的发病机制,可为制定更有效的干预策略提供启示。在这项研究中,我们分析了转录组学数据,以确定在肌肉疏松症发生过程中参与骨骼肌代谢调控的特定基因。我们采用了三种机器学习算法来筛选与新陈代谢密切相关的关键目标基因,并利用 RNA 序列数据和可公开获取的数据集对这些基因进行了进一步验证。其中,代谢酵素烟酰胺 N-甲基转移酶(NNMT)在肌肉疏松症中升高,预测肌肉疏松症的曲线下面积超过 0.7,表明它是治疗肌肉疏松症的潜在靶点。不出所料,抑制 NNMT 能改善衰老小鼠的握力,缓解与年龄相关的股四头肌质量指数和全身瘦肉质量指数的下降。此外,NNMTi 治疗还提高了烟酰胺腺嘌呤二核苷酸(NAD+)含量,以及 D-半乳糖处理小鼠模型和自然衰老小鼠模型肌肉中 PGC1α 和 p-AMPK 的表达水平。总之,这项工作证明了 NNMT 是预防与年龄相关的肌肉质量和力量下降的一个很有前景的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Identification of nicotinamide N-methyltransferase as a promising therapeutic target for sarcopenia

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.

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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
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