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,Kèvin Knoops,Marc Van Bilsen,Blanche Schroen

doi:10.1016/j.omtn.2018.12.010

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.

Highlights

The heart is the most metabolically demanding organ within the body due to its specialized function and limited capacity for energy substrate storage
To study the effect of the inhibition of miR-103/107 on cardiac function and metabolism of unstressed hearts, antagomiR-103 and -107 was injected into adult mice (Figure 1A)
We explored the effect of the antagomiR103 and -107 on systemic metabolism, and we monitored circulating free fatty acid, triglyceride, and glucose levels over the course of 6 weeks

Summary

Introduction

The heart is the most metabolically demanding organ within the body due to its specialized function and limited capacity for energy substrate storage. Approximately 70% of the energy demand is covered by the mitochondrial oxidation of fatty acids, while the remaining 30% stems from carbohydrates, ketones, lactate, and amino acids.[1] The ATP generated in this way is mainly consumed by the myofibrillar actin-myosin ATPase for the contraction/ relaxation of the cardiac muscle and by the Ca2+ ATPase for calcium reuptake in the sarcoplasmatic reticulum.[2] Without tightly controlled energy supply and expenditure, cardiac function becomes severely compromised,[2] and derangements of cardiac substrate and energy metabolism are considered to play a key role in the pathogenesis of heart failure. These miRNAs are, considered promising therapeutic targets for the treatment of diabetes; a clinical phase I or IIA trial with antagomiR-103 and -107 to treat patients with type 2 diabetes and liver disease is currently ongoing (ClinicalTrials.gov: NCT02826525)

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