A study in mice by researchers from the Center for Cardiovascular Research (CNIC) has shown that breast milk provides an essential signal that triggers cardiometabolic maturation after birth, allowing the neonatal heart to function properly and ensuring birth later survival.


Research has shown that the fatty acid gamma-linolenic acid (GLA) present in breast milk binds to the retinoid X receptor (RXR) protein in heart cells. RXRs act as nutrient sensors for lipids and vitamin A derivatives, altering gene expression and affecting biological functions such as immunity, cell differentiation, and metabolism. Once activated by maternal GLA, RXR initiates a genetic program to supply enzymes and other proteins to the mitochondria (the energy centers of the cell) and to begin consuming lipids (the main energy source of the mature heart).


Study leader Dr. Mercedes Ricote, Head of the Nuclear Receptor Signaling Group at the CNIC, explains that the findings may have important therapeutic implications for cardiovascular diseases involving mitochondrial and metabolic dysfunction, as well as for diseases associated with altered postnatal developmental processes.


The team found that in a mouse model, a lack of RXR in the heart or GLA in breast milk prevented mitochondria in the hearts of newborn mice from producing energy properly, leading to severe heart failure and death 24-48 hours after birth.


The heart of a newborn mammal must rapidly generate energy to sustain cardiac contractions outside the womb. To achieve this, cardiomyocytes, the contractile cells of the heart muscle, need to activate their mitochondria, using lipids as an energy source to generate ATP (adenosine triphosphate—the basic energy currency of the cell). Although this process is essential for the survival of the organism, until now little was known about the signals that trigger physiological adaptations in the heart after birth.


Dr Ricote explained: “Maintaining a continuous, uninterrupted heartbeat requires a huge energy demand on the heart. To meet the energy demand, cardiomyocytes maintain tight control over the cellular pathways that generate energy. Any imbalance in these bioenergetic mechanisms can potentially leading to the development of serious cardiovascular disease.”


For Dr. Ricote, the novelty of this research is “demonstrating that RXR plays a key role in the heart muscle, contrary to previous thinking. This is an important conceptual advance in the field of nuclear receptors.”


According to first author Ana Paredes, Ph.D., the study provides a new framework for understanding the postnatal adaptations that occur in newborn mammals to meet the demands of the extrauterine environment. “Birth is a physiological challenge for newborns, and with this study we found that, in addition to its nutritional function, breast milk can also signal by instructing cardiomyocytes to activate their metabolism as they are no longer supported by maternal physiology. ”


The research involved a multidisciplinary approach and advanced sequencing technologies, including important contributions from the CNIC team led by José Antonio Enríquez, Dr Fátima Sánchez-Cabo and Dr Jesús Vázquez.


Taken together, this study demonstrates that the fatty acid GLA found in breast milk is a key signal for ensuring proper heart function after birth. GLA activates the cellular protein RXR, which then directs coordinated gene expression changes to ensure the maturation of cardiomyocyte mitochondria, enabling them to generate energy in the extrauterine environment.


The results open the way for the use of specific drugs to modulate RXR activity in cardiomyocytes, including some already approved by the US Federal Drug Administration for cancer treatment. Dr. Ricote concluded: “Our study proposes RXR as a possible therapeutic target for neonatal heart disease and systemic diseases triggered by metabolic errors.”


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