exmir -129-3p通过抑制PARP1改善线粒体活性增强肌肉功能

IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY
Yeo Jin Shin, Jae Won Yang, Heeyeon Jeong, Joyeong Kim, Bora Lee, Ji-Won Kim, Seung-Min Lee, Ju Yeon Kwak, Young Hoon Son, Kap Jung Kim, Yong Ryoul Yang, Chuna Kim, Ki-Sun Kwon, Kwang-Pyo Lee
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引用次数: 0

摘要

体育锻炼对包括骨骼肌在内的各个器官都有有益的影响。然而,并不是所有的患者都能够通过运动来维持肌肉功能,这就强调了识别体育训练的分子机制的重要性,这可能会导致发现运动模拟分子。方法本研究试图确定运动的分子介质,可以改善肌肉功能。我们关注运动诱导的microRNA (miR)-129-3p,研究其在体内和体外对线粒体活性的作用和影响。分析运动后骨骼肌中miR-129-3p的表达,并阐明其对聚(adp -核糖)聚合酶-1 (Parp1)-SIRT1-PGC1α信号通路的下游作用。通过在成年小鼠中肌肉特异性过表达miR-129-3p和在肥胖小鼠中肌内注射AAV9-miR-129-3p进行功能研究,以评估运动能力和肌肉力量。结果发现运动可上调骨骼肌中miR-129-3p (p < 0.05),直接抑制主要的NAD+消耗酶Parp1。这种抑制导致NAD+水平升高(p < 0.05),激活SIRT1,随后降低PGC1α的乙酰化,从而增强线粒体功能。成年小鼠肌肉特异性过表达miR-129-3p可显著增强运动能力(> 130%, p < 0.0001),而注射AAV9-miR-129-3p可改善肌肉无力(抽搐力,> 140%, p < 0.05;肥胖小鼠破伤风力为160%,p < 0.01)。在人类骨骼肌成肌细胞中,miR-129-3p通过PARP1-SIRT1-PGC1α信号通路改善线粒体功能。我们的研究结果表明,运动诱导的miR-129-3p可以模拟体育锻炼的有益效果。这突出了miR-129-3p作为改善肌肉健康的潜在治疗靶点,特别是在无法运动的个体中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

ExermiR-129-3p Enhances Muscle Function by Improving Mitochondrial Activity Through PARP1 Inhibition

ExermiR-129-3p Enhances Muscle Function by Improving Mitochondrial Activity Through PARP1 Inhibition

Background

Physical exercise has beneficial effects on various organs, including skeletal muscle. However, not all patients are capable of engaging in exercise to maintain muscle function, which underscores the importance of identifying molecular mechanisms of physical training that could lead to the discovery of exercise-mimicking molecules.

Methods

This study sought to identify molecular mediators of exercise that could improve muscle function. We focused on the exercise-induced microRNA (miR)-129-3p, investigating its role and effects on mitochondrial activity both in vivo and in vitro. The expression of miR-129-3p was analysed in skeletal muscle following exercise, and its downstream effects on the poly (ADP-ribose) polymerase-1 (Parp1)-SIRT1-PGC1α signalling pathway were elucidated. Functional studies were conducted using muscle-specific overexpression of miR-129-3p in adult mice and intramuscular injection of AAV9-miR-129-3p in obese mice to assess exercise capacity and muscle strength.

Results

Exercise was found to upregulate miR-129-3p in skeletal muscle (p < 0.05), which directly inhibits Parp1, a major NAD+-consuming enzyme. This inhibition leads to increased NAD+ levels (p < 0.05), activating SIRT1 and subsequently reducing the acetylation of PGC1α, thereby enhancing mitochondrial function. Muscle-specific overexpression of miR-129-3p in adult mice significantly enhanced exercise capacity (> 130%, p < 0.0001), while AAV9-miR-129-3p injections ameliorated muscle weakness (twitch force, > 140%, p < 0.05; tetanic force, > 160%, p < 0.01) in obese mice. In human skeletal muscle myoblasts, miR-129-3p improved mitochondrial function via the PARP1-SIRT1-PGC1α signalling pathway.

Conclusion

Our findings suggest that miR-129-3p, induced by exercise, can mimic the beneficial effects of physical exercise. This highlights miR-129-3p as a potential therapeutic target for improving muscle health, especially in individuals unable to exercise.

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来源期刊
Journal of Cachexia Sarcopenia and Muscle
Journal of Cachexia Sarcopenia and Muscle MEDICINE, GENERAL & INTERNAL-
CiteScore
13.30
自引率
12.40%
发文量
234
审稿时长
16 weeks
期刊介绍: The Journal of Cachexia, Sarcopenia and Muscle is a peer-reviewed international journal dedicated to publishing materials related to cachexia and sarcopenia, as well as body composition and its physiological and pathophysiological changes across the lifespan and in response to various illnesses from all fields of life sciences. The journal aims to provide a reliable resource for professionals interested in related research or involved in the clinical care of affected patients, such as those suffering from AIDS, cancer, chronic heart failure, chronic lung disease, liver cirrhosis, chronic kidney failure, rheumatoid arthritis, or sepsis.
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