The aging modulator miR-29 is essential for adult cardiomyocyte function

Aging is the main risk factor for cardiovascular diseases, underscoring the need to identify the molecular regulators that sustain cardiac function during aging. The microRNA miR-29 is a well-established aging-associated regulator as its expression increases with age, and its overexpression promotes premature aging. Here, we define the cardiomyocyte-autonomous role of miR-29 in the adult heart by generating an inducible, cardiomyocyte-specific miR-29-deficient mouse model (Heart-iKO). We show that Heart-iKO mice develop dilated cardiomyopathy (DCM) with reduced ejection fraction that ultimately leads to premature death. Mechanistically, Heart-iKO cardiomyocytes exhibit alterations in mitochondrial structure and function. Transcriptomic profiling of bulk heart tissue and isolated cardiomyocytes revealed a consistent downregulation of genes involved in oxidative phosphorylation and the electron transport chain. We further observed a similar pattern of mitochondrial impairment in miR-29-deficient human cardiomyocytes derived from induced pluripotent stem cells (CM-iPSCs). Together, these findings highlight the context-dependent role of miR-29 in cardiac physiology and aging: although its upregulation promotes premature aging, its basal expression is required to maintain mitochondrial homeostasis and prevent heart failure in the adult myocardium.