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

Roiz-Valle, D.; Folgueira, C.; Moledo-Nodar, L.; Tartiere, A. G.; Cicuendez, B.; Romero-Becerra, R.; Rodriguez, F.; He, Y.-W.; Freije, J. M. P.; Sabio, G.; Lopez-Otin, C.; Caravia, X. M.; P. Ugalde, A.

doi:10.64898/2026.04.24.718944

bioRxiv · 10.64898/2026.04.24.718944

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

Roiz-Valle, D.·Folgueira, C.·Moledo-Nodar, L.·Tartiere, A. G.·Cicuendez, B.·Romero-Becerra, R.·Rodriguez, F.·He, Y.-W.·Freije, J. M. P.·Sabio, G.·Lopez-Otin, C.·Caravia, X. M.·P. Ugalde, A.

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Abstract

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.

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Roiz-Valle, D., Folgueira, C., Moledo-Nodar, L., Tartiere, A. G., Cicuendez, B., Romero-Becerra, R., Rodriguez, F., He, Y.-W., Freije, J. M. P., Sabio, G., Lopez-Otin, C., Caravia, X. M., P. Ugalde, A.. 2026-04-28. The aging modulator miR-29 is essential for adult cardiomyocyte function. https://doi.org/10.64898/2026.04.24.718944

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