MicroRNA-103/107 regulate systemic glucose metabolism and insulin sensitivity. For this reason, inhibitory strategies for these microRNAs are currently being tested in clinical trials. Given the high metabolic demands of the heart and the abundant cardiac expression of miR-103/107, we questioned whether antagomiR-mediated inhibition of miR-103/107 in C57BL/6J mice impacts on cardiac function. Notably, fractional shortening decreased after 6 weeks of antagomiR-103 and -107 treatment. This was paralleled by a prolonged systolic radial and circumferential time to peak and by a decreased global strain rate. Histology and electron microscopy showed reduced cardiomyocyte area and decreased mitochondrial volume and mitochondrial cristae density following antagomiR-103 and -107. In line, antagomiR-103 and -107 treatment decreased mitochondrial OXPHOS complexes’ protein levels compared to scrambled, as assessed by mass spectrometry-based label-free quantitative proteomics. MiR-103/107 inhibition in primary cardiomyocytes did not affect glycolysis rates, but it decreased mitochondrial reserve capacity, reduced mitochondrial membrane potential, and altered mitochondrial network morphology, as assessed by live-cell imaging. Our data indicate that antagomiR-103 and -107 decrease cardiac function, cardiomyocyte size, and mitochondrial oxidative capacity in the absence of pathological stimuli. These data raise concern about the possible cardiac implications of the systemic use of antagomiR-103 and -107 in the clinical setting, and careful cardiac phenotyping within ongoing trials is highly recommended.

MicroRNA-103 / 107调节全身性葡萄糖代谢和胰岛素敏感性。因此，目前正在临床试验中测试这些microRNA的抑制策略。考虑到心脏的高代谢需求和miR-103 / 107丰富的心脏表达，我们质疑C57BL / 6J小鼠中antagomiR介导的miR-103 / 107抑制是否影响心脏功能。值得注意的是，antagomiR-103和-107治疗6周后，缩短的分数减少了。这与延长的收缩期径向和周向峰时间以及降低的整体应变率相平行。组织学和电子显微镜检查显示，在antagomiR-103和-107之后，心肌细胞面积减少，线粒体体积和线粒体cr密度降低。排队，通过基于质谱的无标记定量蛋白质组学评估，与扰乱的相比，antagomiR-103和-107处理降低了线粒体OXPHOS复合物的蛋白质水平。通过活细胞成像评估，MiR-103 / 107对原代心肌细胞的抑制作用不会影响糖酵解速率，但会降低线粒体储备能力，降低线粒体膜电位，并改变线粒体网络形态。我们的数据表明antagomiR-103和-107在没有病理刺激的情况下会降低心脏功能，心肌细胞大小和线粒体的氧化能力。这些数据引起人们对临床环境中全身使用antagomiR-103和-107可能对心脏造成的影响，强烈建议在正在进行的试验中仔细进行心脏表型分析。