妊娠晚期宫内高血糖通过CREB/PGC1A信号传导导致雄性后代骨骼肌线粒体功能障碍

IF 4.6 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Yi-Shang Yan, Jia-Ying Mo, Yu-Tong Huang, Hong Zhu, Hai-Yan Wu, Zhong-Liang Lin, Rui Liu, Xuan-Qi Liu, Ping-Ping Lv, Chun Feng, Jian-Zhong Sheng, Min Jin, He-Feng Huang
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引用次数: 0

摘要

背景:母体糖尿病会影响后代的发育。妊娠糖尿病(GDM)会给后代造成短期的宫内高血糖环境,导致后代葡萄糖不耐受,但其对后代骨骼肌功能障碍的长期影响和具体机制仍有待明确:方法:将妊娠小鼠分为两组:方法:将妊娠小鼠分为两组:GDM 组在妊娠 6.5 天和 12.5 天腹腔注射 100 毫克/千克链脲佐菌素,对照(CTR)组使用缓冲液。只有从妊娠日 13.5 开始随机血糖水平高于 16.8 mmol/L 的妊娠小鼠才被视为 GDM 组。监测后代的生长情况,并在不同时间点进行葡萄糖耐量试验。采用身体成分分析和免疫组化方法评估 8 周时瘦体重的发育情况。同期还评估了雄性小鼠后代的运动能力和握力。透射电子显微镜用于观察小鼠8周时和胎儿时期骨骼肌内部的形态。我们还研究了与线粒体生物生成和氧化代谢相关的基因和蛋白质。我们还共同分析了 RNA 测序和蛋白质组学数据,以探索其潜在机制。我们还进行了染色质免疫共沉淀和亚硫酸氢盐转化 DNA 甲基化检测,以评估这一现象:结果:短期宫内高血糖抑制了雄性后代的生长并降低了其瘦体重,导致其耐力运动能力下降。GDM雄性后代胫骨前肌的肌纤维组成中,糖酵解成分增多,氧化成分减少。GDM雄性后代骨骼肌中线粒体的形态和功能遭到破坏,胎儿骨骼肌的RNA测序和蛋白质组学共同分析表明,线粒体元素和脂质氧化持续受损。体内和体外成肌细胞实验也表明,高浓度葡萄糖会阻碍线粒体的组织和功能。重要的是,与线粒体生物发生和氧化代谢相关的基因转录在 8 周时和胎儿期减少。我们借助 IPA 软件预测 Ppargc1α 是一个关键的上游调节因子。GDM雄性后代骨骼肌中的Ppargc1α蛋白和mRNA水平在胎儿期(CTR vs. GDM, 1.004 vs. 0.665, p = 0.002)、6周(1.018 vs. 0.511, p = 0.023)和8周(1.006 vs. 0.596, p = 0.018)均有所下降。此外,GDM 组的 CREB 磷酸化受到抑制,与 Ppargc1α (1.042 vs. 0.681, p = 0.037)、Pck1 (1.091 vs. 0.432, p = 0.014) 和 G6pc (1.118 vs. 0.472, p = 0.027) 的 CRE 元结合的活化 pCREB 蛋白减少,导致其转录减少。有趣的是,我们发现肌肉疏松症和线粒体功能障碍甚至会遗传给下一代:结论:短期宫内高血糖会显著降低男性后代 8 周时的瘦体重,导致运动耐力下降和代谢紊乱。在他们中间还观察到骨骼肌线粒体的组织和功能紊乱。胎儿暴露于高血糖状态会降低磷酸化 CREB 的比率,减少 Ppargc1α 的转录,从而抑制线粒体生物生成和氧化代谢下游基因的转录。在 F2 代中也观察到异常线粒体,这可能是通过异常配子传播的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Intrauterine hyperglycaemia during late gestation caused mitochondrial dysfunction in skeletal muscle of male offspring through CREB/PGC1A signaling.

Intrauterine hyperglycaemia during late gestation caused mitochondrial dysfunction in skeletal muscle of male offspring through CREB/PGC1A signaling.

Background: Maternal diabetes mellitus can influence the development of offspring. Gestational diabetes mellitus (GDM) creates a short-term intrauterine hyperglycaemic environment in offspring, leading to glucose intolerance in later life, but the long-term effects and specific mechanism involved in skeletal muscle dysfunction in offspring remain to be clarified.

Methods: Pregnant mice were divided into two groups: The GDM group was intraperitoneally injected with 100 mg/kg streptozotocin on gestational days (GDs) 6.5 and 12.5, while the control (CTR) group was treated with vehicle buffer. Only pregnant mice whose random blood glucose level was higher than 16.8 mmol/L beginning on GD13.5 were regarded as the GDM group. The growth of the offspring was monitored, and the glucose tolerance test was performed at different time points. Body composition analysis and immunohistochemical methods were used to evaluate the development of lean mass at 8 weeks. The exercise capacity and grip strength of the male mouse offspring were assessed at the same period. Transmission electron microscopy was used to observe the morphology inside skeletal muscle at 8 weeks and as a foetus. The genes and proteins associated with mitochondrial biogenesis and oxidative metabolism were investigated. We also coanalyzed RNA sequencing and proteomics data to explore the underlying mechanism. Chromatin immunoprecipitation and bisulfite-converted DNA methylation detection were performed to evaluate this phenomenon.

Results: Short-term intrauterine hyperglycaemia inhibited the growth and reduced the lean mass of male offspring, leading to decreased endurance exercise capacity. The myofiber composition of the tibialis anterior muscle of GDM male offspring became more glycolytic and less oxidative. The morphology and function of mitochondria in the skeletal muscle of GDM male offspring were destroyed, and coanalysis of RNA sequencing and proteomics of foetal skeletal muscle showed that mitochondrial elements and lipid oxidation were consistently impaired. In vivo and in vitro myoblast experiments also demonstrated that high glucose concentrations impeded mitochondrial organisation and function. Importantly, the transcription of genes associated with mitochondrial biogenesis and oxidative metabolism decreased at 8 weeks and during the foetal period. We predicted Ppargc1α as a key upstream regulator with the help of IPA software. The proteins and mRNA levels of Ppargc1α in the skeletal muscle of GDM male offspring were decreased as a foetus (CTR vs. GDM, 1.004 vs. 0.665, p = 0.002), at 6 weeks (1.018 vs. 0.511, p = 0.023) and 8 weeks (1.006 vs. 0.596, p = 0.018). In addition, CREB phosphorylation was inhibited in GDM group, with fewer activated pCREB proteins binding to the CRE element of Ppargc1α (1.042 vs. 0.681, p = 0.037), Pck1 (1.091 vs. 0.432, p = 0.014) and G6pc (1.118 vs. 0.472, p = 0.027), resulting in their decreased transcription. Interestingly, we found that sarcopenia and mitochondrial dysfunction could even be inherited by the next generation.

Conclusions: Short-term intrauterine hyperglycaemia significantly reduced lean mass in male offspring at 8 weeks, resulting in decreased exercise endurance and metabolic disorders. Disrupted organisation and function of the mitochondria in skeletal muscle were also observed among them. Foetal exposure to hyperglycaemia decreased the ratio of phosphorylated CREB and reduced the transcription of Ppargc1α, which inhibited the transcription of downstream genes involving in mitochondrial biogenesis and oxidative metabolism. Abnormal mitochondria, which might be transmitted through aberrant gametes, were also observed in the F2 generation.

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来源期刊
Nutrition & Diabetes
Nutrition & Diabetes ENDOCRINOLOGY & METABOLISM-NUTRITION & DIETETICS
CiteScore
9.20
自引率
0.00%
发文量
50
审稿时长
>12 weeks
期刊介绍: Nutrition & Diabetes is a peer-reviewed, online, open access journal bringing to the fore outstanding research in the areas of nutrition and chronic disease, including diabetes, from the molecular to the population level.
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