Identification of the key catalyst for muscle energy production

Researchers have investigated the role of a specific enzyme in regulating muscle energy and exercise performance for decades, but a new study by Virginia Tech scientists has pinpointed more precisely than ever how this mechanism works.

Scientists working at the Fralin Biomedical Research Institute at VTC focused on an activation event that leads to the activation of AMPK, which is a major energy sensor known as adenosine monophosphate-activated protein kinase. It is a regulator of energy production in response to the enormous energy demands of exercise.

The study, published on Wednesday, February 25, 2026, in Advances in Scienceconfirmed the role of AMPK phosphorylation at a single amino acid in regulating the quantity and activity of mitochondria, power-generating organelles in cells. But the researchers also found an unexpected broader range of regulation, including muscle contraction and the breakdown of sugar for energy, pointing toward a potential new treatment for diabetes.

“The data suggest that AMPK is not only important for maintaining mitochondrial quantity but also for regulating other processes leading to mitochondrial metabolism and regulating protein function for muscle contraction.”

Zhen Yan, Lead Study Author and Professor, Fralin Biomedical Research Institute, Virginia Tech

Yan is director of FBRI’s Center for Exercise Medicine Research.

Ryan Montalvo, a postdoctoral fellow in the Yan Lab and first author of the paper, said the study builds on the strengths of an interdisciplinary research team.

“These findings not only deepen our understanding of how exercise affects metabolic health,” he said, “but also open up new directions for future studies that our lab has already begun to pursue.”

With exercise, muscles require more energy to keep going. The AMPK enzyme senses demand and responds by sending signals to cells to increase the amount and activity of mitochondria to meet future energy demands.

Yan and his team used gene-editing technology to turn off a cell signaling site they believed was key to how AMPK responds to increased energy demand. They did this without disrupting the structure of the AMPK protein and its partner proteins.

The mice in the study showed dramatically reduced exercise capacity, running only a third of the distance of typical mice. With cell signaling turned off, the enzyme could not do its job to meet the energy demand in muscle cells, confirming that the signaling site of the disabled cells is crucial to the process.

The study provides a more detailed understanding of how the AMPK mechanism works than previously known.

In addition to the study data, Montalvo analyzed proteins in mouse skeletal muscle against similar data from people with diabetes and found significant overlap. This could suggest that reduced function of the AMPK enzyme could play a role in diabetes.

“This suggests that if we target AMPK with drug interventions, we may be able to help diabetic patients,” said Yan, who is also a professor in the Department of Human Nutrition, Food and Exercise at Virginia Tech’s College of Agriculture.

This study focused on outcomes during exercise. Yan aims to further investigate AMPK by looking at its role in exercise adaptation – how muscles change in response to exercise to become fitter and make exercise easier in the future.