X染色体剂量驱动着他类药物诱导的失糖症和线粒体功能障碍
Peixiang Zhang1,2, Joseph J Munier3, Carrie B Wiese1
1Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Nature communications
|July 2, 2024
概括
像糖尿病和女性肌肉衰弱等他类药物的副作用与较低的omega-3 docosahexaenoic acid (DHA) 水平有关. 补充DHA或调整X染色体剂量可以防止这些不良反应.
科学领域:
- 生物化学 生物化学
- 遗传学 遗传学 是一个
- 药理学 药理学是指药理学的学科.
背景情况:
- 类药物被广泛用于通过降低血中的胆固醇来预防心血管疾病.
- 与男性相比,女性对他类药物的不良影响,包括新发糖尿病 (NOD) 和肌肉衰弱的发病率更高.
- 对性别特异性他类药物不良影响的潜在机制仍然不完全理解.
研究的目的:
- 调查女性增加他类药物的不良影响背后的分子机制.
- 确定潜在的治疗策略,以减轻女性的他类药物引起的并发症.
主要方法:
- 对接受他类药物治疗的雄性和雌性小鼠进行比较分析,重点关注葡萄糖平衡,肌肉功能和多可萨赫萨酸 (DHA) 水平.
- 评估受影响组织中的氧化还原声和线粒体呼吸.
- 评估鱼油 (DHA来源) 的治疗潜力和X染色体剂量调节 (Kdm5c基因) 在预防不良影响方面.
- 在体外研究使用诱导多能干细胞 (iPSC) 来自NOD的男性和女性患者.
主要成果:
- 在雌性小鼠中,他类药物治疗导致葡萄糖稳定性受损和肌肉衰弱,与降低的DHA水平,降低的氧化还原度和减少的线粒体呼吸有关.
- 在雌性小鼠中,服用鱼油 (DHA) 或减少X染色体剂量/Kdm5c基因表达可以防止他类药物诱导的不良反应.
- 与男性相比,女性在施用他类药物后的DHA水平下降更大,并且在DHA和葡萄糖水平之间存在逆相关性.
- 静止剂治疗在NOD女性的iPSC中损害了线粒体功能,但在男性的iPSC中没有.
结论:
- 降低的DHA水平和线粒体功能受损,可能与X染色体剂量有关,导致女性对他类药物的不良影响.
- 补充DHA和调节X染色体基因剂量代表了对敏感个体的他类药物相关并发症的有前途的预防性联合治疗.
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