The latest scientific research by the Max Planck Institute for Heart and Lung Research in Bad Nauheim (Germany) has further shown that the potential for heart muscle regeneration lies in metabolic reprogramming. The energy metabolism of the human heart depends on the following factors: substrate availability, oxygen pressure and cardiac workload. This background explains why one of the main challenges of current cardiology is the development of new therapies aimed at the molecular and cellular mechanism of heart failure. Within the latter, this in mice reprogramming research resulting in the regeneration of cardiac muscle cells by the inactivation of the Cpt1b gene (essential for fatty acid oxidation) appears to be a promising mechanism to develop.
During a heart attack, heart muscle cells die and scar tissue forms, paving the way for heart failure. Cardiovascular disease is a leading cause of death worldwide, in part because the cells in our most vital organ fail to renew themselves and regain their function. Unlike blood, hair and skin cells, which can renew themselves throughout our lives, heart cells stop dividing shortly after birth, and later, as adults, their regeneration is minimal. As per statistics around 805,000 people in the United States experience a heart attack every year. Some key risks of heart disease include, high blood pressure, high blood cholesterol, diabetes, smoking, excessive alcohol use, obesity, physical inactivity and several other medical conditions.
In order to understand the regeneration process of heart muscles it is important to review the maturation of the cardiac energy metabolism of the human heart. The fetal human heart namely uses glucose as its primary substrate, also known as the process of glycolysis. This energy process enables the fetal heart to regenerate in case of muscle damage also known as mitosis (process of cell replication). However, shortly after birth a metabolic change occurs as the heart switches to fatty acid oxidation to obtain more energy in order to pump sufficient blood throughout the body. Due to this switch the activitation of various genes change and the ability to regenerate is lost. Glucose, lactate and fatty acids are the primary source of energy production in the adult heart. Pyruvate (end product of glycolysis) is converted to lactate or transported to the mitochondria where it is decarboxylated and converted to acetyl-CoA. Fatty acids are transported to the cytoplasm and activated to their respective fatty acyl-CoA by fatty acyl-CoA synthetase (AGCS). Fatty acyl-CoA is converted to fatty acyl-carnitine by cartinine palmitoyl transferase I (CPT I), translocated across the inner membrane of the mitochondria by acyl translocase (CAT), and then fatty acyl-carnitine is converted to fatty acyl-CoA by carnyl palmitoyl transferase II (CPT II). Intramitochondrial fatty acyl-CoAs are degraded by β-oxidation. Acetyl-CoA from glycolysis or β-oxidation enter the Krebs cycle. The NADH2 and FADH generated in the Krebs cycle serve as substrates for the electron transport chain (ETC). This process requires oxygen and is responsible for the generation of the proton gradient necessary for ATP synthesis.
The approach for this experiment was straightforward, namely in mice energy metabolism reprogramming to trigger gene activity and regain the ability for cardiac muscle cell division. The first step was to deactivate the Cpt1b gene. A clear observation during this proccess was rapid heart muscle cell growth, almost doubling the pre-experimental amount of heart muscle cells. The researchers then mimicked an heart attack (occlusion of the coronary arteries) in these mice by first reducing the blood flow and then flushing the heart with oxygenated blood. As a result, the heart regenerated functional heart muscle cells with minimal scarring and the heart muscle contractility of the Cpt1b-deactivated mice nearly returned to pre-infarction levels. The underlying mechanism of the rapid cardiac cell growth in Cpt1b-deactivated mice was the increase of α-Ketoglutarate molecules (important for cellular activity and protein synthesis) which increased the activition of the KDM5 enzyme. KDM5 is a histone demethylase, which removes tri- and di- methyl groups from lysine 4 on histone H3 (H3K4) and reduces particular gene activation. As a result the heart muscle cells become immature and revert to fetal cardiac energy metabolism. Thus regaining the ability to regenerate.
In conclusion, the regeneration of heart muscles requires the reprogramming of the cardiac energy metabolism to its fetal activity by ensuring the inhibition of the Cpt1b gene. This deactivation causes an increase in KDM5 enzymes and consequently the immaturation of heart muscle cell. Ultimately resulting in a cardiac energy metabolism based greatly on glycolysis. A future treatment for heart infarction could, therefore, be a Cpt1b gene inhibitor.
References:
Cardiac regeneration becomes possible. (n.d.). https://www.mpg.de/20981292/1020-pfor-cardiac-regeneration-becomes-possible-through-reprogramming-of-cell-metabolism-149770-x?c=2249
School of Medicine and Public Health [University of Wisconsin-Madison]. (2021, April 16). Metabolic switch may regenerate heart muscle following heart attack. https://www.med.wisc.edu/news-and-events/2021/april/metabolic-switch-may-regenerate-heart-muscle/
Li, X., Wu, F., Günther, S. et al. Inhibition of fatty acid oxidation enables heart regeneration in adult mice. Nature 622, 619–626 (2023). https://doi.org/10.1038/s41586-023-06585-5
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