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The Secret to Secretariat’s Speed?

By Adam Marcus

The ability of racehorses to sprint at top speed for extended periods has fascinated observers and mystified scientists. A new study in Science may reveal how equids evolved into such powerhouses.

Horses were not always such elegant or seemingly tireless runners. As the fossil record indicates, early equids were small—about the size of a large dog—with bodies that did not appear particularly impressive. Today, the typical Thoroughbred is a 4-hooved engine with a mane, able to use energy-providing oxygen twice as efficiently as an Olympic athlete.

In essence, equids (and birds) have evolved a remarkably efficient way of neutralizing key byproducts of muscle activity—reactive oxygen species (ROS)—which are produced by mitochondria in muscle when they use oxygen.

“This oxidative process fuels energy production, akin to a fire that oxidizes wood. But that comes at a cost, which is all of the smoke, known as oxidative stress,” said Gianni M. Castiglione, PhD, an assistant professor in the Departments of Biological Sciences, Ophthalmology & Visual Sciences at Vanderbilt University, in Nashville, Tenn., who led the research. “Our paper shows horses evolved a mutation that lets this fire burn hotter—generating more energy—while producing less smoke” in the form of oxidative stress.

Although genomic analyses of equids have shown some potentially significant mutations that differentiate horses from humans and other mammals, none fully explain the horse’s massive advantage in oxygen metabolization and energy generation.

The new findings stem from previous research in birds, which showed the avian genome experienced mutations in a master regulatory pathway, NRF2/KEAP1, that led to the upregulation of an array of genes involved in the suppression of the effects of oxidation on cells. The net effect of these mutations—particularly those in the NRF2/KEAP1 pathway—was to give avian muscles the ability to better tolerate oxidative stress during exercise.

Given the importance of the NRF1/KEAP1 pathway to endurance, the researchers hypothesized equids may have undergone similar changes as birds at some point in their evolution.

“The NRF2/KEAP1 pathway is a fundamental metabolic and stress pathway that was recognized to be preserved across the entire animal kingdom, including fish,” said Elia Duh, MD, a specialist in eye disease at Johns Hopkins University, in Baltimore, and the senior author of the new study.

The researchers found that equids underwent a similar genomic transformation to birds, at least in terms of NRF1/KEAP1, which gave them a supercharged ability to muzzle oxidative stress. At the same time, the researchers also found signs of another effect of the mutations: the increased production of adenosine 5’-triphosphate (ATP), the key energy molecule in mammals, and an increase in the ability of mitochondria to consume oxygen.

Dr. Castiglione said horses have a hair-trigger response to ROS, reacting to the slightest signal of the molecules at the start of exercise by switching on the antioxidant system. “The flood of ROS that results from full-blown exercise is extremely damaging to muscles, and horses make a lot of ROS during exercise, so we theorize that this is why the priming system of the KEAP1 hair-trigger evolved,” he said.

While this system confers enormous advantages, it does have trade-offs, the researchers said. Horses may be more likely to experience so-called “reductive stress”—the opposite of oxidative stress—caused by an excess of antioxidative activity. As a result, exercise is particularly important for them, Dr. Castiglione said. “Their body’s homeostatic set point is adapted to exercise, so a sedentary lifestyle may be especially problematic, as the NRF2 system has nothing to fight against,” he said. MeV

For more information:
Castiglione GM, Chen X, Xu Z, et al. Running a genetic stop sign accelerates oxygen metabolism and energy production in horses. Science. 2025;387(6741). doi: 10.1126/science.adr8589. https://www.science.org/doi/10.1126/science.adr8589