Mother’s Milk Nurses Heart Cells to Maturity in Mice
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Researchers from the Spanish National Centre for Cardiovascular Research (NCIC) discovered that a fatty acid found in mother’s milk helps mouse pups’ hearts to mature. The study is published in Nature.
From sugar to fat
Baby mammals’ hearts must produce sufficient energy to enable contraction of the heart muscle – a big metabolic task.
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In the womb, the cells of the heart – known as cardiomyocytes – gobble up glucose to produce this energy. After birth, a “switching” occurs, which sees cardiomyocytes burning lipids instead for the rest of the mammal’s lifetime. “The need to maintain a constant and uninterrupted beat places an immense energy demand on the heart,” explains Dr. Mercedes Ricote, a biologist at NCIC. "To meet their energy needs, cardiomyocytes maintain a tight control over the cellular pathways that produce energy. Any imbalance in these bioenergetic mechanisms can lead to the development of serious cardiovascular pathologies."
The challenge for scientists such as Ricote, who studies nuclear receptor signaling, was that the cellular mechanisms responsible for reshaping the cardiomyocytes’ fuel preferences were unknown. Alongside her colleagues at NCIC, she embarked on a seven-year-long quest to find answers.
Fatty acid helps reshape heart cells’ fuel preference
The research team fed pups milk from mothers eating standard mouse chow and a second cohort fed fat-free chow. The pups eating the fat-free chow developed cardiac issues and, in many cases, died. This experiment pointed towards the mother’s diet – and therefore the components of their milk – as a potential area of interest for mouse pup heart development.
Analyzing the molecular constituents of the milk, Ricote and colleagues identified one essential fatty acid – called ɣ-linolenic acid or GLA – which pups can only obtain through ingesting breast milk. When the mothers’ fat-free chow was supplemented with GLA, the pups receiving the milk “thrived”, according to the research paper. GLA binds to a protein called retinoid X receptor (RXR) found in cardiomyoctes. In the laboratory model, the absence of RXR expression in the heart adversely affected the heart health of the pups. “Multifaceted genome-wide analysis revealed that the lack of RXR in embryonic cardiomyocytes caused an aberrant chromatin landscape that prevented the induction of an RXR-dependent gene expression signature controlling mitochondrial fatty acid homeostasis,” the authors write in the paper.
Without GLA binding to RXR and providing the mitochondria with essential enzymes and proteins required to consume lipids, the heart cells lack the energy to develop and stay healthy.
Implications for treating neonatal heart disorders
According to Ricote, the impact of the study “lies in demonstrating that RXR plays a critical role in cardiac muscle, contrary to what was previously thought. This is an important conceptual advance in the field of nuclear receptors."
As the study used laboratory models, it remains to be seen whether GLA plays such a role in the development of human cardiomyocytes. If the research translates, modulating RXR activity using pharmacological agents could offer new avenues for treating neonatal heart disorders, Ricote emphasizes.
Reference: Paredes A, Justo-Méndez R, Jiménez-Blasco D, et al. γ-Linolenic acid in maternal milk drives cardiac metabolic maturation. Nature. 2023. doi: 10.1038/s41586-023-06068-7
This article is a rework of a press release issued by the Spanish National Centre for Cardiovascular Research. Material has been edited for length and content.