Ketogenic Gene Therapy Allows Heart Regeneration and Rejuvenation
Heart disease is the leading cause of death worldwide, with myocardial infarction (heart attack) being the most common cause. Heart transplantation is still the optimal treatment for the disease, but there are insufficient donors to meet the demands. In mammals, including humans, cardiac muscle cells (cardiomyocytes) cannot keep dividing and forming new cells after birth, meaning we are unable to regenerate the heart after injury. However, some animals such as salamander and zebrafish can successfully regenerate the heart after injury, using a process called “dedifferentiation”. A new study from Taiwanese researchers has shown that ketone production in the heart links to this dedifferentiation process and can allow for regeneration after injury. This study was recently published in Circulation.
Prof. Patrick CH Hsieh, the corresponding author said: “Under normal conditions our heart cells mainly use fat as an energy source, but we knew that following injury our heart cells will look for additional sources, including ketones. Our research found that by inducing ketone production in the cardiomyocytes of adult mice we not only kept more cells alive – we actually allowed dedifferentiation and proliferation to occur. We then identified the key enzyme (HMGCS2) which enables all of this to happen.”
The researchers used genetically edited mice to examine how HMGCS2 affects heart function. By reducing or removing HMGCS2 function in mice the animals showed poorer heart function after injury, again confirming the importance of HMGCS2. This result was recapitulated in human induced pluripotent stem cell (iPSC)-derived cardiomyoctes. The authors also created a potential gene therapy by showing that HMGCS2 delivery improved heart function after injury.
The first author Dr. Yuan-Yuan Cheng said: “Ketones are usually supplied by the liver, and the heart is always described as a ketone receiver. However, we found that inducing ketone generation in the heart not only provides more energy for the cells, but it creates metabolic adaptation which is essential for heart regeneration. In our study we found that only the injured area of the heart showed the metabolic switch and our gene therapy treatment did not adversely affect the other areas of the heart. Therefore, I hope that in the future, we may be able to use this metabolic adaptation as a treatment for patients suffering from myocardial infarction.”
The study entitled “Metabolic Changes Associated with Cardiomyocyte Dedifferentiation Enable Adult Mammalian Cardiac Regeneration” is published online in Circulation. The research team is led by Dr. Patrick CH Hsieh at Academia Sinica, Taiwan, in collaboration with the great scientists in Taiwan and USA, including Dr. Tim Kamp of the University of Wisconsin-Madison and Dr. Rong Tian at the University of Washington, Seattle. The study is funded by the Academia Sinica, National Science and Technology Council, National Health Research Institutes, and the University of Wisconsin–Madison.
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Dr. Yuan-Yuan Cheng, Institute of Biomedical Sciences, Academia Sinica
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