Mouse hearts can regenerate by blocking an energy transfer enzyme
A new pre-clinical study may have found a secret to unlocking cardiac regeneration in mammal hearts to repair infarct damage. The discovery could eventually lead to drugs that could help repair human hearts. The study was published this week in the journal Nature Cardiovascular Research.[1]
Some animals like the zebrafish can completely regenerate lost or damaged heart muscle within weeks to months after an injury. The phenomenon has been a focus of research for years. Now researchers have found newborn mouse hearts can regenerate up to a week after birth, leading researchers to ask if this ability could be turned on again later in life.
The new work is sponsored by the National Institutes of Health (NIH) and led by Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, with collaborators across the U.S. In the study report, the team details how treatment enhances regeneration and cardiac function in mice. They found changing the way heart cells produce energy triggers coordinated changes in gene regulation across multiple cell types, promoting regeneration and improving recovery after a heart attack.
The research team had previously found blocking an enzyme called succinate dehydrogenase could flip a metabolic switch in adult heart cells in mice. This reset the animals' metabolism to mimic how they produce energy in the neonatal stage, prompting cardiomyocytes to promote regeneration.
“Normally, mice lose the ability to regenerate their hearts just like humans and other mammals,” said senior and corresponding author Ahmed Mahmoud, PhD, interim director and associate professor in the Center for Cardiovascular and Muscular Diseases at Sanford Burnham Prebys, said in a statement. “After our treatment, we observed cardiac cells proliferating once again along with the formation of new blood vessels and a reduction in scar tissue that normally follows a heart attack.”
He added that the most pronounced change was a suppression of scar-formation cardiac fibroblasts.
To better understand how the process works and what is happening inside the cells, the research team used sequencing techniques to measure changes in gene expression and DNA accessibility in mice treated with a metabolite called malonate, which blocks succinate dehydrogenase.
“We found that regions of DNA associated with pro-regenerative and cell cycle genes became more accessible in heart muscle cells, making it easier for the cell to activate these programs,” said co-first author Yi Fan, PhD, a postdoctoral associate in the Mahmoud lab at Sanford Burnham Prebys, in a statement.
These observations led the team to focus experiments on these cell types. They found blocking succinate dehydrogenase in cardiomyocytes produced a transient increase in their proliferation, but this alone was not enough to improve cardiac function after a heart attack. However, they found blocking the enzyme in cardiac fibroblasts suppressed their activation and reduced scar formation, resulting in improved cardiac function.
The findings also highlight the importance of timing. Unlike sustained genetic disruption of succinate dehydrogenase activity, malonate temporarily inhibits the enzyme, potentially allowing heart cells to enter a regenerative state and then return to the mature metabolic state needed for normal cardiac function.
“It is a multicellular effect that’s driving regeneration, which is something we couldn’t fully appreciate until we isolated the effects of metabolic reprogramming in different cell types,” said Mahmoud.
He explained metabolic reprogramming appears to reawaken several features of the regenerative response normally seen in the neonatal heart. This, he said, could translate into a long-term goal to develop a therapy to treat the more than 800,000 people in the U.S. who experience a heart attack each year. This is seen as a holy grail in cardiology, where drug therapies could reverse myocardial infarctions or other types of heart damage and head off heart failure.
Dave Fornell has covered healthcare for more than 17 years, with a focus in cardiology and radiology. Fornell is a 5-time winner of a Jesse H. Neal Award, the most prestigious editorial honors in the field of specialized journalism. The wins included best technical content, best use of social media and best COVID-19 coverage. Fornell was also a three-time Neal finalist for best range of work by a single author. He produces more than 100 editorial videos each year, most of them interviews with key opinion leaders in medicine. He also writes technical articles, covers key trends, conducts video hospital site visits, and is very involved with social media. E-mail: [email protected]