Fatty acids in mouse milk trigger maturation of cardiac metabolism

In a study in mice led by scientists at the National Cardiovascular Research Center (CNIC), components of breast milk are key signals that promote maturation of the neonatal heart metabolism after birth, enabling the neonatal heart to function. was found to provide Correctly, ensuring survival after birth.

In this study, the fatty acid (FA) gamma-linolenic acid (GLA) in breast milk binds to retinoid X receptors (RXR) on heart cells (cardiomyocytes), triggering the maturation of the cells’ mitochondria and allowing the cells to utilize lipids. was shown to generate mitochondria. ATP. Pups bred to lack her RXR in cardiac cells or fed milk without GLA died shortly after birth.

The results may have therapeutic implications for cardiovascular diseases involving mitochondrial and metabolic dysfunction, as well as diseases associated with changes in postnatal developmental processes, said CNIC nuclear receptor signaling. Lead researcher Dr. Mercedes Ricote, who leads the transmission group, suggested.

Ricote and an international research team reported on their findings: Nature, In a paper titled “”γ-Linolenic acid in breast milk promotes metabolic maturation of the heart“Our findings support the emerging view that early childhood mother-infant interactions are a major driver of biological physiology and highlight the importance of breast milk feeding for mitochondrial maturation in the perinatal heart.” , and this finding has major implications for heart health,” the researchers said. ”

Mammalian hearts require a continuous supply of energy to maintain contraction, and cardiomyocytes exhibit what the authors called a “very flexible metabolism” that can contain glucose, lipids, lactate, amino acids, etc. A wide range of substrates can be consumed to produce cardiac function. ATP (adenosine triphosphate) is used as the essential energy currency of the cell.

Fetal cardiomyocytes are primarily dependent on the oxidation of glucose and lactate, whereas the main source of postnatal ATP generation is mitochondrial lipid oxidation. Although this process is crucial for an organism’s survival, scientists know very little about the signals that drive physiological adaptations in the heart after birth.

“The fetal-to-neonatal cardiac switch is thought to occur gradually during the first two weeks of life, culminating in a functional mitochondrial compartment where fatty acids are efficiently oxidized by β-oxidation 7 (FAO). ,” the researchers explained. However, while this adaptation step is critical for maintaining heart rate and survival, “little is known about the molecular mechanisms and upstream signals that direct this metabolic transition.”

A new study in mice found that GLA in breast milk binds to the retinoid X receptor (RXR) on neonatal cardiomyocytes, triggering the cells’ mitochondrial maturation. RXR functions as a nutrient sensor for lipids and vitamin A derivatives, altering gene expression and affecting biological functions such as immunity, cell differentiation, and metabolism. In this study, RXR, when activated by maternal GLA, supplies the cell’s mitochondria with the enzymes and other proteins necessary to initiate the consumption of lipids, the main source of energy in the mature heart. It turned out that the program was started.

Studies have shown that in a mouse model in which the RXR gene is deleted in the fetal heart (fetal double knockout, EDKO animals), lack of RXR in cardiac cells allows mitochondria in the heart of newborn animals to produce energy correctly. becomes incapacitated, develops severe heart failure, and dies shortly after birth. “…80% of EDKO puppies died within 24 hours of birth, and no EDKO neonates survived past the seventh day of life,” the research team wrote.

Similarly, wild-type newborn mice that drank milk from mothers fed a fat-free diet (FFD) also died within 48 hours of birth. Taken together, their findings indicate that milk-FA supports metabolic adaptations in the neonatal heart, and that activation of the milk-FA-RXR axis is relevant to perinatal life support. suggesting that it is a mechanism,” the researchers said.

Subsequent in vitro studies identified GLA as a ligand for RXR, and further experiments in mice showed that neonates born to mothers on a fat-free diet thrived when breast milk was supplemented with GLA. I was. Of note, pups delivered to mothers fed regular chow also died when suckled on FFD milk, suggesting that “as an adequate source of GLA to ensure perinatal survival, It supports a role for breast milk rather than lipid deposition during pregnancy,” the researchers said. further pointed out.

Taken together, the findings demonstrate that the fatty acid GLA in breast milk is an important signal to ensure correct cardiac function after birth. GLA activates the cellular protein RXR, which subsequently directs coordinated gene expression changes to ensure that cardiomyocyte mitochondria mature and are ready to produce energy in the extrauterine environment.

“The heart demands an enormous amount of energy because it has to maintain a constant, uninterrupted heartbeat,” Ricote explained. “To meet their energy needs, cardiomyocytes tightly control the cellular pathways that generate energy. Imbalances in these bioenergetic mechanisms can lead to the development of severe cardiovascular disease.”

For Ricote, part of the novelty of the study “is that it demonstrates that RXR plays an important role in the myocardium, contrary to what was previously thought.” This is an important conceptual advance in the field of nuclear receptors. ”

According to lead author Ana Paredes, PhD, the study presents a new framework for understanding the postnatal adaptations that occur in neonatal mammals to meet the requirements of the extrauterine environment. “Birth is a physiological challenge for newborns,” Paredes explained. “This study shows that, in addition to its nutritional function, breast milk also plays a role in signaling to myocardial cells that they are no longer supported by maternal physiology and therefore need to be metabolically active. ”

The results pave the way for therapies that modulate RXR activity in cardiomyocytes using specific agents, including those already FDA-approved for cancer treatment. “Our study suggests RXR as a potential therapeutic target for neonatal heart disease and systemic disease caused by metabolic errors,” he concluded Dr. Ricote. And from a “nutritional perspective,” the research team concluded, “Low amounts of GLA in human breast milk are associated with impaired growth in neonates, suggesting a potential role for this fatty acid in human neonatal physiology. I do,’ he commented.