Switching what the powerhouses of coronary heart cells eat for vitality might assist the guts regenerate when cells die, a brand new examine led by UT Southwestern researchers suggests. The discovering, printed within the Feb. 20, 2020, Nature Metabolism, might open complete new avenues for treating a wide range of circumstances during which coronary heart muscle turns into broken, together with coronary heart failure attributable to viruses, toxins, hypertension, or coronary heart assaults.
Current pharmaceutical remedies for coronary heart failure — together with ACE inhibitors and beta blockers — middle on making an attempt to cease a vicious cycle of coronary heart muscle loss as pressure additional damages remaining coronary heart muscle, inflicting extra cells to die, explains UT Southwestern physician-researcher Hesham A. Sadek, M.D., Ph.D., the J. Fred Schoellkopf, Jr. Chair in Cardiology. There aren’t any present remedies for rebuilding coronary heart muscle.
Nine years in the past, Sadek and his colleagues found that mammalian hearts can regenerate in the event that they’re broken within the first few days of life, spurred by the division of cardiomyocytes, the cells chargeable for a coronary heart’s contractile pressure. However, this capability is totally misplaced by 7 days previous, an abrupt turning level during which division of those cells dramatically slows.
Subsequent analysis has proven that this variation in regenerative capability seems to stem, not less than partly, from damaging free radicals generated by organelles often called mitochondria, which energy cells. These free radicals harm cells’ DNA, a phenomenon known as DNA harm, which prompts them to cease dividing.
The shift in free radical manufacturing seems to be spurred by a change in what mitochondria within the cardiomyocytes eat for vitality, Sadek explains. Although mitochondria depend on glucose in utero and at beginning, they swap to fatty acids within the days after beginning to make the most of these energy-dense molecules in breast milk.
Sadek and his colleagues questioned whether or not forcing mitochondria to proceed to eat glucose may stymie DNA harm and, in flip, lengthen the window for coronary heart cell regeneration. To take a look at this concept, the researchers tried two totally different experiments.
In the primary, they adopted mouse pups whose moms had been genetically altered to provide low-fat breastmilk and that consumed low-fat chow after they weaned. The researchers discovered that these rodents’ hearts maintained regenerative capability weeks later than regular, with their cardiomyocytes persevering with to specific genes related to cell division for a considerably longer window than these fed a eating regimen of standard breastmilk and chow. However, this impact did not final into maturity — their livers finally made up the deficit by synthesizing the fat that their diets had been lacking, which considerably diminished their hearts’ regenerative capability.
In the second experiment, the researchers created genetically altered animals during which the researchers might delete an enzyme, often called pyruvate dehydrogenase kinase 4 (PDK4), mandatory for the guts cells’ mitochondria to digest fatty acids. When the researchers delivered a drug to show off PDK4 manufacturing, the animals’ cardiomyocytes switched to consuming glucose as an alternative of fatty acids, even in maturity. After researchers simulated a coronary heart assault, these animals skilled enchancment in coronary heart operate, which was accompanied by markers in gene expression that urged their cardiomyocytes had been nonetheless actively dividing.
Sadek notes that these findings present proof of precept that it is attainable to reopen the window for coronary heart cell regeneration by manipulating what cardiomyocyte mitochondria eat for vitality.
“Eventually,” he says, “it could be attainable to develop medicine that change what cardiomyocytes eat to make them divide once more, reversing coronary heart failure and representing a real treatment.”