A fatty acid present in breast milk is essential for the maturation of the heart in newborn mice, according to an article published in Nature. The findings of this study led by researchers from the National Center for Cardiovascular Research (CNIC) shed more light on the mechanisms of how environmental factors affect the development of the hearts of newborn mice after birth.
Research has revealed that breast milk intake is the essential signal for the metabolically mature neonatal heart after birth, allowing the heart to function properly and ensuring postnatal survival.
Specifically, it is the omega-and-6 fatty acid intake of breast milk, in addition to its nutritional function, plays a role signaler warning cardiomyocytes that they should activate their metabolism, because they are no longer supported by maternal-linolenic physiology (GLA) from breast milk, which is responsible for binding to the cell protein Retinoid X Receptor (RXR). RXR is a protein that acts as a nutritional sensor for lipids and vitamin A derivatives, altering gene expression and influencing important biological functions such as immunity, cell differentiation or metabolism. Once RXR detects maternal GLA, it sets in motion genetic programs that equip mitochondria, the cells’ powerhouses, with the proteins needed to begin consuming lipids, the main source of energy in the mature heart.
Birth presents challenges to a newborn’s heart, requiring various changes and maturation of heart cells. For example, cardiomyocytes, the contractile cells of the heart, need to remodel their fuel preference from glucose to fatty acids so that the heart can beat efficiently throughout life. However, the mechanisms underlying this maturation process are not well understood.
The results could have vast therapeutic implications in cardiovascular pathologies where there are mitochondrial and metabolic dysfunctions, as well as diseases related to alterations in maturational processes after birth, says Mercedes Ricote, head of the Nuclear Receptor Signaling Group of the CNIC and leader of the investigation.
GLA cannot be synthesized by mice (or humans), so it must be ingested. Newborn mice fed milk from mothers on a fat-free diet could not survive more than two days after birth; however, supplementation of this milk with GLA restored normal survival in neonates.
The researchers also identified retinoid X receptors on cardiomyocytes as the target for GLA to bind and activate to initiate the process of metabolic maturation of heart muscle cells.
In addition, it has been shown, in a mouse model, that both the absence of RXR in the heart, and the lack of the omega-6 fatty acid GLA in breast milk, prevent mitochondria from producing energy correctly, leading to severe heart failure. that ends up causing death 24-48 hours after birth.
Research shows that ingesting breast milk plays a signaling role, telling cardiomyocytes to activate their metabolism
At birth, the baby’s heart should begin to quickly produce energy to initiate the heartbeat in the extrauterine environment. To do this, cardiomyocytes, myocardial contractile cells, need to activate mitochondria, ATP-generating organelles (adenosine triphosphate or adenosine triphosphate) that support the cell’s bioenergetic pathways. Although this process is essential for the survival of the organism, until now there was very little information about the signals that trigger the physiological adaptation of the heart after childbirth.
“The need to maintain a constant and uninterrupted heartbeat means that the heart requires high energy inputs,” explains Mercedes Ricote. “To meet their energy needs, heart cells have very tight control of the cellular pathways that produce energy. However, any imbalance in these bioenergetic mechanisms can lead to the appearance of serious cardiovascular pathologies.
For Ricote, the novelty of this work “also resides in the fact that It is the first time that it has been shown thatContrary to what was believed, RXR plays an essential role in the heart muscle. This finding represents a very important conceptual advance in the scientific field of nuclear receptors.”
The research, whose main author is Ana Paredes, proposes a very novel angle to understand the postnatal adaptations that are triggered for the organism to meet the requirements in the extrauterine environment. “Birth constitutes a physiological challenge for the newborn,” says Paredes. “With this work we demonstrate that the intake of breast milk, in addition to its nutritional function, plays a signaling role, warning cardiomyocytes that they must activate their metabolism, because maternal physiology no longer supports them.”
The results may have therapeutic implications in cardiovascular pathologies where there are mitochondrial and metabolic dysfunctions.
In conclusion, the researchers point out, the study shows that GLA, which comes from breast milk but is also present in formula milk that contains the gamma-linolenic acid (GLA) precursor, linoleic acid (LA), is the signal key to the heart working properly after birth. GLA activates the cellular protein Retinoid X Receptor (RXR), and as a result, mitochondria mature for cardiomyocytes to produce energy in the extrauterine environment.
The results, the researchers emphasize, open up the possibility of modulating RXR activity in cardiac cells through the use of specific drugs, some of them approved by the US health authorities (FDA) for the treatment of some cancers. “Our work proposes RXR as a potential therapeutic target in neonatal heart diseases, and in systemic pathologies caused by metabolic failures”, concludes Ricote.