期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 14, 期 -, 页码 424-437出版社
CELL PRESS
DOI: 10.1016/j.omtn.2018.12.010
关键词
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资金
- Netherlands Organisation for Scientific Research (NWO) (VIDI grant) [917.14.363, 016.176.340]
- Netherlands Heart Foundation [2014T105, 2015T082]
- Health Foundation Limburg
- ERA-CVD Joint International Call grant (Netherlands Heart Foundation)
- ERA-CVD Joint International Call grant (NWO-ZonMw grant) [2016T091]
- Marie Curie action program CardiomiR FP7-MC-IAPP [285991]
- Royal Netherlands Academy of Sciences [CVON 2011-11 ARENA]
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.
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