Delivery of muscle-derived exosomal miRNAs induced by HIIT improves insulin sensitivity through down-regulation of hepatic FoxO1 in mice
Delivery of muscle-derived exosomal miRNAs induced by HIIT improves insulin sensitivity through down-regulation of hepatic FoxO1 in mice
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DOI：
10.1073/pnas.2016112117
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发表时间：
2020-12-08
影响因子：
11.1
通讯作者：
Parrizas, Marcelina
中科院分区：
文献类型：
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作者：
Castano, Carlos;Mirasierra, Mercedes;Parrizas, Marcelina
通过尚未完全确定的分子机制，实施有规律的体力活动有助于维持人类和小鼠的健康代谢。在这里，我们证明了高强度间歇训练(HIIT)改变了小鼠循环外切体的microRNA(MiRNA)谱，包括miR-133a和miR-133b的显著增加。重要的是，用从训练小鼠的血浆中分离出来的外切体治疗久坐的小鼠可以改善葡萄糖耐量、胰岛素敏感性，并降低血浆甘油三酯水平。此外，从训练过的小鼠肌肉中分离出的外切体在miRNA含量上也显示出类似的变化，给久坐的小鼠服用它们可以重现葡萄糖耐量的改善。HIIT靶向胰岛素调节转录因子叉头盒O1(FoxO1)上调外体miRNAs，相应地，FoxO1在训练和外切体处理的小鼠肝脏中的表达降低。用带有miR-133b模拟物的外切体或针对FoxO1的特定siRNA进行治疗，可以重述在训练小鼠中观察到的代谢效应。总体而言，我们的数据表明，肌肉释放的循环外切体携带一种特定的miRNA信号，该信号可被运动修改，并诱导肝脏表达变化，影响全身代谢谱。
Implementation of regular physical activity helps in the maintenance of a healthy metabolic profile both in humans and mice through molecular mechanisms not yet completely defined. Here, we show that high-intensity interval training (HIIT) modifies the microRNA (miRNA) profile of circulating exosomes in mice, including significant increases in miR-133a and miR-133b. Importantly, treatment of sedentary mice with exosomes isolated from the plasma of trained mice improves glucose tolerance, insulin sensitivity, and decreases plasma levels of triglycerides. Moreover, exosomes isolated from the muscle of trained mice display similar changes in miRNA content, and their administration to sedentary mice reproduces the improvement of glucose tolerance. Exosomal miRNAs up-regulated by HIIT target insulin-regulated transcription factor forkhead box O1 (FoxO1) and, accordingly, expression of FoxO1 is decreased in the liver of trained and exosome-treated mice. Treatment with exosomes transfected with a miR-133b mimic or with a specific siRNA targeting FoxO1 recapitulates the metabolic effects observed in trained mice. Overall, our data suggest that circulating exosomes released by the muscle carry a specific miRNA signature that is modified by exercise and induce expression changes in the liver that impact whole-body metabolic profile.