How AMPK Enzyme Drives Exercise Performance

For decades, scientists have sought to clarify the role of a key enzyme in exercise performance and energy transduction in skeletal muscle. Now, investigators at Virginia Tech’s Fralin Biomedical Research Institute have pinpointed how the enzyme Adenosine Monophosphate-Activated Protein Kinase, or AMPK, orchestrates this process at a detailed molecular level.

Their study, published in Science Advances, focused on a specific event that activates AMPK, a master energy sensor regulating how cells respond to the demands of exercise. Researchers confirmed that phosphorylation of AMPK at a single amino acid is essential for controlling both the quantity and activity of mitochondria—the energy-producing organelles within cells. They also uncovered evidence that AMPK influences a wider range of processes, including muscle contraction and the breakdown of sugar for energy, suggesting the enzyme could be a future therapeutic target 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,” explained lead author Zhen Yan.

To test AMPK’s role, the team used gene-editing tools to switch off a specific cellular signaling site believed to control how the enzyme responds to increased energy demand during exercise. Importantly, this modification left AMPK’s structure and partner proteins intact. Mice with the signaling site switched off showed severely reduced endurance, running only about one-third as far as normal mice. This outcome confirmed the site’s crucial function in enabling the enzyme to sense and meet muscle energy needs.

Further protein analyses revealed significant overlap between the mouse results and data from human diabetic patients. Yan noted that diminished AMPK activity might contribute to diabetes, adding that targeting this enzyme with drugs could potentially help manage the disease. His team now plans to study how AMPK participates in exercise adaptation—how muscles become stronger and more efficient over time.