AntagomiR-103 and-107 Treatment Affects Cardiac Function and Metabolism

Monika Rech, Annika R. Kuhn, Joost Lumens, Paolo Carai, Rick van Leeuwen, Wouter Verhesen, Robin Verjans, Julie Lecomte, Yilin Liu, Joost J. F. P. Luiken, Ronny Mohren, Berta Cillero-Pastor, Stephane Heymans, Kevin Knoops, Marc van Bilsen, Blanche Schroen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)424-437
Number of pages14
JournalMolecular Therapy - Nucleic Acids
Volume14
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • SPECKLE TRACKING ECHOCARDIOGRAPHY
  • HEART-FAILURE
  • MICRORNA
  • DYSFUNCTION
  • INSULIN
  • HYPERTROPHY
  • EXPRESSION
  • TISSUES

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