Researchers headed by a team at the University of Pennsylvania have found that exercise does more than strengthen muscles, it also rewires the brain. Studying mice, the investigators discovered that the lasting gain in endurance from repeated exercise—such as the ability to run farther and faster over time—involves changes in brain activity that help muscles and hearts to become stronger. Their results linked the metabolic adaptations that boost endurance to the activity of a group of neurons known as SF1 neurons, in the ventromedial hypothalamus (VMH).
“When we lift weights, we think we are just building muscle,” says J. Nicholas Betley, PhD, at the University of Pennsylvania department of biology. “It turns out we might be building up our brain when we exercise.”
Betley is corresponding author of the researchers’ published paper in Neuron, titled “Exercise-induced activation of ventromedial hypothalamic steroidogenic factor-1 neurons mediates improvements in endurance.” In their paper the team concluded “By emphasizing the role of the CNS, particularly VMH SF1 neurons, this work suggests that central neural adaptations contribute more significantly to endurance than previously recognized.”
“Physical exercise engages adaptive mechanisms that facilitate future exercise performance (colloquially referred to as endurance) and improves physiological function,” the authors wrote. “The benefits from exercise training result from the remodeling of skeletomuscular, cardiovascular, metabolic, and endocrine systems.” And while exercise is associated with remodeling of brain circuits, these adaptations have been presumed to reflect, rather than produce, the endurance benefits that result from repeated exercise.
“A lot of people say they feel sharper and their minds are clearer after exercise,” said Betley, “So we wanted to understand what happens in the brain after exercise and how those changes influence the effects of exercise.”
Through their experiments with mice, Betley and colleagues noticed that animals had increased brain activity after running on the treadmill, especially in the neurons located in the ventromedial hypothalamus (VMH). This brain region plays an important role in how the body uses energy, including regulating body weight and blood sugar. “Excitatory neurons in the ventromedial hypothalamus (VMH) express the orphan nuclear receptor and transcription factor steroidogenic factor-1 (SF1),” the team explained. SF1 expression is required during development for correct differentiation of VMH neurons and maintenance of energy homeostasis in adulthood. “SF1-expressing VMH neurons integrate peripheral signals such as leptin, insulin, and glucose to regulate energy expenditure.”
By monitoring neural activity in mice, the team found that this specific group of SF1 neurons became active when the animals ran on a treadmill. These neurons also stayed active for at least an hour after the mice finished running. After daily exercise for two weeks mice showed improvement in endurance. They were able to run faster and longer before becoming exhausted. When researchers looked at the animals’ brains, they saw that more SF1 neurons became active, and the activity levels were significantly higher than at the beginning of training. “Repeated exercise increases both the number of VMH SF1 neurons activated and the magnitude of their activation,” they reported.
When the team blocked SF1 neuron activity and prevented them from sending signals to the rest of the brain, these animals got tired quickly and showed no improvements in endurance over the two-week training period. To the researchers’ surprise, blocking SF1 neurons only after exercise also prevented endurance gains even though the neurons functioned normally during exercise itself. “Inhibiting SF1 neural activity following exercise training blocks subsequent improvements in endurance capacity,” they stated. This result suggests the important role for SF1 activity after exercise.
While the underlying mechanism remains unclear, Betley says that active SF1 neurons post-exercise may help the body recover faster by using glucose stored in the body more efficiently. This may allow other parts of the body—like the muscle, lungs, and heart—to adapt more quickly to harder workouts. “Taken together, these data suggest a prominent role for VMH SF1 neuron activity in controlling body-wide responses to repeated exercise and suggest a central role for the brain in mediating peripheral metabolic adaptations during and after exercise training,” the investigators concluded. “… We find that SF1 neuron activity is essential for appropriately engaging energy stores, activating skeletomuscular remodeling during exercise, and enhancing endurance with repeated training.”
Betley hopes that this research could one day help older people or people recovering from stroke stay active while also benefiting athletes and younger people recovering from injury. “This study opens the door for understanding how we can get more out of exercise,” he said. “If we can shorten the timeline and help people see benefits sooner, it may encourage them to keep exercising.”
In their paper the team stated, “This line of investigation raises the intriguing possibility of developing exercise mimetics that activate VMH SF1 neurons or their downstream pathways, offering a novel strategy to enhance endurance and metabolic function in populations unable to engage in regular physical activity.”
