Cell signaling step sharpens understanding of how the body responds to exercise’s energy demands

Researchers have investigated the role of a certain enzyme in regulating energy in muscle and exercise performance for decades, but a new study by Virginia Tech scientists has identified more precisely than ever how this mechanism works. Scientists working at the Fralin Biomedical Research Institute at VTC focused on a triggering event that leads to the activation of AMPK, a master energy sensor known as adenosine monophosphate-activated protein kinase. It is a regulator of energy production in response to the tremendous energetic demands of exercise.

The study, published in Science Advances, confirmed the role of AMPK phosphorylation within a single amino acid in regulating the quantity and activity of mitochondria, organelles that generate power in the cells. But the researchers also found an unexpected wider range of regulation, including muscle contraction and breaking down sugar for energy, pointing toward a potential new treatment for diabetes.

“The data suggest that AMPK is not only important for maintaining the quantity of mitochondria but also regulating other processes leading to mitochondrial metabolism and regulation of protein function for muscle contraction,” said Zhen Yan, a professor with Virginia Tech’s Fralin Biomedical Research Institute at VTC and the paper’s lead author. Yan is the director of FBRI’s Center for Exercise Medicine Research.

Ryan Montalvo, a postdoctoral associate in the Yan Lab and the paper’s first author, said the study draws on the strengths of a multidisciplinary research team.

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

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

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

The mice in the study showed a dramatically diminished ability to exercise, running only about a third of the distance of typical mice. With cellular signaling switched off, the enzyme was unable to do its job in responding to the demand for energy in muscle cells, confirming that the switched-off cell signaling site is vital to the process.

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

In addition to the study data, Montalvo analyzed proteins in the skeletal muscle of mice over similar data from human diabetic patients and found significant overlap. That could indicate that reduced AMPK enzyme function could play a role in diabetes.

“That 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 Virginia Tech’s Department of Human Nutrition, Foods, and Exercise in the College of Agriculture.

This study focused on effects during exercise. Yan aims to further investigate AMPK by examining its role in exercise adaptation—how muscles change in response to exercise to become more fit and make exercise easier in the future.