Prepregnancy Obesity Reprograms Offspring Skeletal Muscle Fibre Transition Through H3K9me3

IF 9.4 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle Pub Date : 2025-04-21 DOI:10.1002/jcsm.13825

Yichi Wu, Sujuan Li, Jingyi Zhang, Anran Tian, Xiangyao Wang, Xi Yang, Fucheng Meng, Qing Li, Yuan Gao, Yingying Li, Furong Liang, Minglan Yao, Xiaoping Luo, Cai Zhang

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引用次数: 0

Abstract

Background

Maternal prepregnancy obesity predisposes offspring to obesity and metabolic disorders, yet its impact on skeletal muscle fibre transition remains unclear. Given that skeletal muscle plays a crucial role in systemic metabolism, we investigated how maternal prepregnancy high-fat diet (HFD) influences muscle fibre composition and metabolic function in offspring.

Methods

We established mouse models with a prepregnancy chow diet (CD) and a prepregnancy high-fat diet (HFD) for 8 weeks to compare metabolic phenotypes in offspring. Skeletal muscles from offspring were analysed using RNA sequencing, quantitative reverse transcription polymerase chain reaction and western blot to understand the changes in metabolic and signalling pathways. siRNA knockdown and lentiviral-mediated overexpression experiments were conducted in vitro and in vivo to validate molecular mechanisms. Chromatin immunoprecipitation followed by qPCR (ChIP-qPCR) was used to assess histone modification levels at promoter regions.

Results

Male and female offspring of prepregnancy obese dams (mHFD) exhibited a significant reduction in slow-twitch oxidative fibres (p < 0.001) and an increase in fast-twitch glycolytic fibres compared with controls. This was accompanied by impaired glucose tolerance (AUC increased by 12.87%, p < 0.01), insulin resistance and mitochondrial dysfunction (mtDNA copy number reduced by 31%, p < 0.01). RNA sequencing identified IDH2 as the most significantly downregulated gene (29.67% decrease, p < 0.001), with protein levels further reduced in male (30.15%, p < 0.01) and female (46.02%, p < 0.0001) offspring. IDH2 knockdown in C2C12 cells impaired mitochondrial biogenesis and led to higher oxidative stress (NADP+/NADPH ratio elevated by 32%, p < 0.01), while IDH2 overexpression restored mitochondrial integrity, enhanced slow-twitch fibre proportion (26.43 ± 0.6936% in mHFD-LV-IDH2, p < 0.01) and improved glucose metabolism (fasting glucose reduced by 14.7%, p < 0.01). ChIP-qPCR revealed increased H3K9me3 enrichment at the IDH2 promoter (2.54-fold in males, 2.55-fold in females, p < 0.0001), suggesting transgenerational epigenetic regulation.

Conclusions

Maternal prepregnancy obesity induces a metabolic shift in offspring skeletal muscle by promoting a slow-to-fast fibre transition and impairing mitochondrial biogenesis. This effect is mediated by IDH2 suppression via H3K9me3 histone modification, contributing to systemic insulin resistance. Targeting IDH2 may represent a potential therapeutic strategy to mitigate metabolic dysfunction in offspring exposed to maternal prepregnancy obesity.

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孕前肥胖通过 H3K9me3 重编程子代骨骼肌纤维的转变

背景孕妇孕前肥胖使其后代易患肥胖和代谢紊乱，但其对骨骼肌纤维转化的影响尚不清楚。鉴于骨骼肌在全身代谢中起着至关重要的作用，我们研究了孕妇孕前高脂肪饮食（HFD）如何影响后代的肌纤维组成和代谢功能。方法建立孕前鼠粮（CD）和孕前高脂饮食（HFD） 8周小鼠模型，比较后代代谢表型。利用RNA测序、定量逆转录聚合酶链反应和western blot对后代骨骼肌进行分析，以了解代谢和信号通路的变化。在体外和体内进行了siRNA敲除和慢病毒介导的过表达实验，以验证分子机制。染色质免疫沉淀和qPCR （ChIP-qPCR）用于评估启动子区域组蛋白修饰水平。结果与对照组相比，孕前肥胖母鼠（mHFD）的雄性和雌性后代表现出慢收缩氧化纤维的显著减少（p < 0.001）和快速收缩糖酵解纤维的增加。同时伴有糖耐量下降（AUC增加12.87%,p < 0.01）、胰岛素抵抗和线粒体功能障碍（mtDNA拷贝数减少31%，p < 0.01）。RNA测序发现IDH2是下调最显著的基因（降低29.67%,p < 0.001），雄性后代和雌性后代的IDH2蛋白水平进一步降低（30.15%,p < 0.01）和46.02%,p < 0.0001)。IDH2在C2C12细胞中表达下调，线粒体生物发生受损，氧化应激升高（NADP+/NADPH比值升高32%，p < 0.01），而IDH2过表达恢复线粒体完整性，增强慢肌纤维比例（mhfd - lc -IDH2中为26.43±0.6936%,p < 0.01），改善葡萄糖代谢（空腹血糖降低14.7%,p < 0.01）。ChIP-qPCR显示，在IDH2启动子处H3K9me3富集增加（雄性为2.54倍，雌性为2.55倍，p < 0.0001），提示存在跨代表观遗传调控。结论孕妇孕前肥胖通过促进纤维从慢到快的转变和损害线粒体生物发生，诱导子代骨骼肌代谢转变。这种作用是通过H3K9me3组蛋白修饰抑制IDH2介导的，有助于全身性胰岛素抵抗。针对IDH2可能是一种潜在的治疗策略，以减轻暴露于母亲孕前肥胖的后代的代谢功能障碍。

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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来源期刊

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.