以网络为基础系统分析运动对老年人骨质疏松的抑制作用

IF 4.7 2区 医学 Q1 NEUROSCIENCES
Hirotaka Iijima, Fabrisia Ambrosio, Yusuke Matsui
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引用次数: 0

摘要

骨骼肌中的脂肪堆积(即肌骨质疏松症)在久坐不动的老年人中很常见,会损害骨骼肌的健康和功能。从机理上理解体力活动水平如何决定脂肪积累,是建立促进健康老龄化疗法的关键一步。本研究采用网络医学范式,描述了老年肌肉对运动和固定方案的转录组反应,探索了调节纤维脂肪生成祖细胞(FAPs)命运的共享分子级联,FAPs是主要造成脂肪积累的细胞群。具体来说,通过网络传播进行的基因组富集分析发现,Pgc-1α是一个大型基因调控网络的功能枢纽,它是老龄肌肉(而非年轻肌肉)中体力活动调控纤维脂肪生成祖细胞的基础。在老年肌肉中诱导 Pgc-1α 过表达的硅学和原位综合方法促进了线粒体脂肪酸氧化并抑制了 FAP 脂肪生成。这些研究结果表明,Pgc-1α-线粒体脂肪酸氧化轴是体力活动调控与年龄相关的肌肉骨质疏松症的共同机制。所引入的网络医学范式提供了对老年骨骼肌运动适应性的机理认识,并提供了促进老年人运动处方的转化机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Network-based systematic dissection of exercise-induced inhibition of myosteatosis in older individuals

Network-based systematic dissection of exercise-induced inhibition of myosteatosis in older individuals

Network-based systematic dissection of exercise-induced inhibition of myosteatosis in older individuals
Accumulated fat in skeletal muscle (i.e. myosteatosis), common in sedentary older individuals, compromises skeletal muscle health and function. A mechanistic understanding of how physical activity levels dictate fat accumulation represents a critical step towards establishment of therapies that promote healthy ageing. Using a network medicine paradigm that characterized the transcriptomic response of aged muscle to exercise versus immobilization protocols, this study explored the shared molecular cascade that regulates the fate of fibro-adipogenic progenitors (FAPs), the cell population primarily responsible for fat accumulation. Specifically, gene set enrichment analyses with network propagation revealed Pgc-1α as a functional hub of a large gene regulatory network underlying the regulation of FAPs by physical activity in aged muscle, but not in young counterparts. Integrated in silico and in situ approaches to induce Pgc-1α overexpression in aged muscle promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. These findings suggest that the Pgc-1α–mitochondrial fatty acid oxidation axis is a shared mechanism by which physical activity regulates age-related myosteatosis. The network medicine paradigm introduced provides mechanistic insight into exercise adaptation in elderly skeletal muscle and offers translational opportunities to advance exercise prescription for older populations.

Key points

  • Fat accumulation is a quintessential feature of aged skeletal muscle.
  • While increasing physical activity levels has been proposed as an effective strategy to reduce the fat in skeletal muscle (i.e. myosteatosis), the molecular cascade underlying these benefits has been poorly defined.
  • This study implemented a series of network medicine approaches and uncovered Pgc-1α as a mechanistic driver of the regulation of fibro-adipogenic progenitors (FAPs) by physical activity.
  • Integrated in silico and in situ approaches to induce Pgc-1α overexpression promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis.
  • Together, the findings of the current study suggest a novel hypothesis that physical activity reduces myosteatosis via upregulation of Pgc-1α-mediated mitochondrial fatty acid oxidation and subsequent inhibition of FAP adipogenesis.
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来源期刊
Journal of Physiology-London
Journal of Physiology-London 医学-神经科学
CiteScore
9.70
自引率
7.30%
发文量
817
审稿时长
2 months
期刊介绍: The Journal of Physiology publishes full-length original Research Papers and Techniques for Physiology, which are short papers aimed at disseminating new techniques for physiological research. Articles solicited by the Editorial Board include Perspectives, Symposium Reports and Topical Reviews, which highlight areas of special physiological interest. CrossTalk articles are short editorial-style invited articles framing a debate between experts in the field on controversial topics. Letters to the Editor and Journal Club articles are also published. All categories of papers are subjected to peer reivew. The Journal of Physiology welcomes submitted research papers in all areas of physiology. Authors should present original work that illustrates new physiological principles or mechanisms. Papers on work at the molecular level, at the level of the cell membrane, single cells, tissues or organs and on systems physiology are all acceptable. Theoretical papers and papers that use computational models to further our understanding of physiological processes will be considered if based on experimentally derived data and if the hypothesis advanced is directly amenable to experimental testing. While emphasis is on human and mammalian physiology, work on lower vertebrate or invertebrate preparations may be suitable if it furthers the understanding of the functioning of other organisms including mammals.
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