Researchers at Sanford Burnham Prebys Medical Discovery Institute published findings on September 28, 2026, in Nature Cardiovascular Research showing that a drug-induced metabolic switch in mice reduces scar tissue and improves heart function after a heart attack by targeting multiple cell types simultaneously.
The mammalian heart famously lacks an internal mechanic. While neonatal mouse hearts can regenerate tissue for up to a week after birth, that regenerative window slams shut as the animals age, leaving adult mammals vulnerable to permanent scarring after a cardiac event such as a heart attack. A research team based at the Sanford Burnham Prebys Medical Discovery Institute and across the United States has now demonstrated that this fix-it power is not necessarily lost forever. By altering how heart cells produce energy, scientists have managed to rouse dormant regenerative programs in adult mice.
Targeting Succinate Dehydrogenase to Reset Cellular Energy
The therapeutic strategy centers on blocking an enzyme known as succinate dehydrogenase. Previous work by the research group established that inhibiting this enzyme effectively flips a metabolic switch in adult heart cells, forcing them to mimic the energy production seen during the neonatal stage. That metabolic reset coaxes mature heart muscle cells to begin proliferating once again.
Mahmoud and colleagues observed that treating injured animals prompted cardiac cells to proliferate, sparked the formation of new blood vessels, and shrank the fibrotic scar tissue that typically overtakes damaged myocardial tissue.
Sequencing DNA Access and Histone Modifications in Treated Mice
To uncover the microscopic shifts driving this recovery, the investigators administered a metabolite called malonate to block succinate dehydrogenase in experimental animals. Using advanced sequencing techniques, the team measured changes in gene expression and tracked how tightly DNA was coiled around protein spools called histones.
At the same time, sequencing revealed that connective tissue cells known as cardiac fibroblasts experienced a distinct suppression of their scar-forming programs. Examining the underlying histone modifications confirmed that activating marks were turned on near regeneration-associated genes in cardiomyocytes, while repressive marks turned down fibrosis genes in fibroblasts.
Genetic Disruption Tests Reveal Distinct Roles for Heart Muscle and Connective Tissue
Because systemic malonate injections circulate throughout the entire vascular system, the team needed to isolate the consequences of enzyme inhibition in specific cell types. To do this, they turned to newly developed mouse models genetically altered to disrupt succinate dehydrogenase activity exclusively in either cardiomyocytes or cardiac fibroblasts.
The genetic tests laid bare an unexpected physiological divide. Selectively blocking the enzyme in heart muscle cells produced only a temporary increase in cell division, and that proliferation alone was not sufficient to improve overall cardiac function. Conversely, disrupting the enzyme in connective tissue cells successfully suppressed scar formation and led to measurable improvements in pumping recovery.
The comparative findings proved that true cardiac repair relies on a coordinated multicellular response rather than a single cell type working in isolation.
Timing and Methodological Details of the Experimental Models
The research published in Nature Cardiovascular Research details precise laboratory protocols involving animal lines including Sdhbfl/fl mice provided by J. Favier at INSERM and wild-type CD-1 mice purchased from Charles River Laboratories. Additional strains such as αMHC-MerCreMer and Postn-MerCreMer lines were sourced from the Jackson Laboratory. Experimental surgeries involved permanent ligation of the left anterior descending coronary artery in eight-week-old mice to model myocardial infarction.
The distinction between temporary pharmacological inhibition and genetic disruption explains why transient therapies hold clinical promise. While genetic knockout locks cells into an altered state, daily injections of malonate temporarily inhibit succinate dehydrogenase. This fleeting window allows cardiac cells to adopt a pro-regenerative metabolic state before safely returning to the mature profile required for normal, long-term heart function.