MiR 208a Deficiency Promotes Mitochondrial Biogenesis in the metabolic heart

Abstract

A high caloric regimen causes metabolic syndrome, which is a pre‐requisite for type 2 diabetes mellitus, and increases the risk for cardiovascular disease. Both metabolic syndrome and diabetes induce a common cardiac phenotype known as metabolic cardiomyopathy with an early onset as diastolic dysfunction that may progress to systolic dysfunction and congestive heart failure.While the normal heart is able to freely switch between glucose and fatty acid (FA) oxidation, the metabolic heart becomes almost completely reliant on FA oxidation for ATP production. This energetic dysregulation is supported by increased mitochondrial metabolism, which includes an increased mitochondrial mass and function. Based on the reported cardiac specificity of the microRNA (miR) 208a, we investigated its role in bioenergetic metabolism in the metabolic heart. Lewis rats exposed to a high fat diet (HFD) exhibit obesity, systemic insulin resistance, hyperglycemia, hyperlipidemia, cardiac diastolic dysfunction, and cardiac fibrosis. Microarray studies highlighted an altered miRNA expression profile in the heart upon HFD, including a decrease in miR 208a. CRISPR deletion of the miR 208a in cultured human SV40 cardiomyocytes exposed to diabetogenic conditions (high glucose, high albumin‐bound palmitate) led to a bioenergetics profile that favors mitochondrial FA metabolism including an increase in mitochondrial biogenesis signaling, electron transport chain complexes and critical enzymes for FA beta‐oxidation. In addition, miR 208‐a deficiency prevented the switch in the myosin heavy chain isoforms by increasing myosin heavy chain alpha, thus preserving cardiac contractility. We analyzed in silico for putative miR 208a targets focusing on mitochondrial outcomes using the TargetScanHuman database ( http://www.targetscan.org/cgi‐bin/targetscan/vert_71/targetscan.cgi). We found that mitochondrial ribosomal protein 28 (involved in mitochondrial translation and generation of mitochondrial DNA‐encoded electron transport chain subunits), MINOS1 (a conserved component of mitofilin complexes required for mitochondrial function and cristae organization), and MED7 (component of the Mediator Complex that regulates the transcription by facilitating the interaction between nuclear receptors, transcriptional co‐activator and co‐repressors, and chromatic modification factors with RNA Pol II) are rescued by miR 208a deficiency in cardiomyocytes exposed to diabetogenic conditions. In summary, miR 208a regulates nuclear and mitochondrial transcription, mitochondrial cristae organization and integrity in the diabetic heart, and supports the metabolic remodeling towards increased FA oxidation. Our data suggest that miR 208a may be a therapeutic target to promote mitochondrial biogenesis in chronic diseases associated with mitochondrial defects.Support or Funding InformationCentral Michigan University Early Career Grant, AIREA American Heart Association