Fatty acid in mouse milk triggers maturation of heart metabolism

A study in mice, conducted by scientists from the Centro Nacional de Investigaciones Cardiovasculares (CNIC), has revealed that a component of breast milk provides an essential signal that triggers the maturation of cardiac metabolism in the newborn after birth, allowing the newborn’s heart to function properly and ensure postnatal survival.

The study showed that the fatty acid (FA) gamma-linolenic acid (GLA) in breast milk binds to the retinoid X receptor (RXR) present on heart cells – cardiomyocytes – triggering the maturation of the cells’ mitochondria so that they use lipids to generate ATP. Puppies bred to lack RXR on their heart cells, or those fed milk containing no GLA, died shortly after birth.

The findings could have important therapeutic implications for cardiovascular disorders involving mitochondrial and metabolic dysfunction, as well as diseases linked to alterations in postnatal developmental processes, suggested study leader Mercedes Ricote, PhD, who leads the study. nuclear receptor signaling group at CNIC.

Ricote and the international team of researchers reported their findings in Nature, in an article titled “γ-linolenic acid in breast milk stimulates cardiac metabolic maturation“, in which they stated, our results reinforce the emerging idea that mother-infant interactions in early life are major drivers of the body’s physiology and underscore the importance of breast milk ingestion. for mitochondrial maturation of perinatal hearts, a finding with major implications for heart health.”

The mammalian heart needs a continuous supply of energy to maintain contraction, and cardiomyocytes exhibit what the authors called a “highly flexible metabolism”, meaning they can consume a wide range of substrates, including glucose, lipids, lactate and amino acids, to generate ATP (adenosine triphosphate) which is used as the essential energy currency of the cell.

Fetal cardiomyocytes depend primarily on the oxidation of glucose and lactate, but after birth the main source of ATP production is the oxidation of mitochondrial lipids. Although this process is crucial for the survival of the organism, scientists know little about the signals that trigger the physiological adaptation of the heart after birth.

“The fetal to neonatal cardiac transition is thought to occur gradually over the first two weeks of life, culminating in a functional mitochondrial compartment in which fatty acids are efficiently oxidized by β-oxidation7 (FAO),” the researchers explained. . But while this adaptive step is critical for maintaining heart rate and survival, “very little is known about the molecular mechanisms and upstream signals that drive this metabolic transition.”

The new study in mice has now revealed that GLA in breast milk binds to the retinoid X receptor (RXR) present on neonatal cardiomyocytes, triggering the maturation of the cells’ mitochondria. RXR acts as a nutritional sensor of lipids and vitamin A derivatives, altering gene expression and influencing biological functions such as immunity, cell differentiation and metabolism. The study found that once activated by maternal GLA, RXR initiates genetic programs that equip cells’ mitochondria with the enzymes and other proteins they need to begin consuming lipids, the main source of energy. of the mature heart.

Studies have shown that in mouse models in which RXR genes have been deleted in the embryonic heart (embryonic double knockout; EDKO animals), the absence of RXR in heart cells prevents mitochondria from the heart of new animals -born to produce energy properly, leading to severe heart failure and death soon after birth. “…80% of EDKO puppies died within the first 24 hours of life, and no EDKO pups survived beyond day 7 after birth,” the team wrote.

Similarly, neonatal wild-type mice breastfed with milk from mothers fed a fat-free diet (FFD) also died within 48 hours of birth. The combined results of their studies indicated that milk-FA supports metabolic adaptation in the neonatal heart, “…and suggests that activation of a milk-FA-RXR axis is a relevant mechanism for the maintenance of perinatal life,” the researchers said.

Later in vitro tests identified GLA as a ligand for RXR, and further experiments in mice showed that newborns of mothers on a fat-free diet thrived when their milk was supplemented with GLA. Notably, puppies born to mothers fed a normal diet also died when sucked with FFD milk, “supporting the role of breast milk, not fat deposits during pregnancy, as source of relevant GLA to ensure perinatal survival”, the investigators. noted later.

The combined results of the study demonstrate that the fatty acid GLA, present in breast milk, is the key signal that ensures proper heart function after birth. GLA activates the cellular protein RXR, which then directs coordinated changes in gene expression to ensure that cardiomyocyte mitochondria mature so they can produce energy in the extrauterine environment.

“The need to maintain a constant, uninterrupted rhythm places an immense energy demand on the heart,” Ricote explained. “To meet their energy needs, cardiomyocytes maintain tight control over cellular pathways that produce energy. Any imbalance of these bioenergetic mechanisms can lead to the development of serious cardiovascular pathologies.

For Ricote, part of the novelty of the study “lies in demonstrating that RXR plays a critical role in heart muscle, contrary to what was previously thought. This is an important conceptual advance in the field of nuclear receptors.

According to first author Ana Paredes, PhD, the study presents 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 the newborn,” Paredes explained. “With this study, we show that breast milk, in addition to its nutritional function, plays a signaling role by indicating to cardiomyocytes that they must activate their metabolism because they are no longer supported by maternal physiology.”

The findings point the way to treatments to modulate RXR activity in cardiomyocytes with specific drugs, some of which already have FDA approval for cancer treatment. “Our study offers RXR as a possible therapeutic target for neonatal cardiac disorders and systemic diseases triggered by metabolic errors,” Ricote concluded. And from a “nutritional perspective,” the team commented, “a low abundance of GLA in human breast milk has been linked to growth deficits in neonates, suggesting a potential role for this fatty acid in human neonatal physiology”.