Exploring exercise's physiological response to fight diabetes

Don't love the gym? Neither does exercise scientist Ryan Montalvo. But he goes anyway.

While any workout can seem daunting, the physical stress of exercise often affords long-term benefits. One advantage is that it triggers a physiological response that allows our cells to adjust to meet future energy demand in what's known as a hormetic response.

With an early career research grant from the American College of Sports Medicine Research Endowment, Montalvo will explore how this response to exercise-induced stress might help overcome noncommunicable diseases.

Working in Professor Zhen Yan's lab at the Fralin Biomedical Research Institute at VTC, Montalvo is investigating the body's adaptations to exercise stress. His research could reveal how cellular changes caused by exercise affect metabolic diseases like diabetes.

"Every time you exercise, you're increasing the demand to your mitochondria, and the exposure to that stress makes you better adapted to that stress the next time you encounter it," Montalvo said. "If your mitochondria adapt to those physiological stressors you've given them through exercise, they can be more effective at mitigating or preventing disease."

Mitochondria are specialized structures within our cells responsible for converting nutrients into adenosine triphosphate, or ATP, which helps power biological processes ranging from muscle contractions during exercise to the biochemical reactions that maintain basic cellular function.

"Mitochondria produce ATP continuously, but they don't automatically know how much ATP to manufacture," Montalvo said. This is because they rely on an energy-sensing molecule to process both intrinsic and extrinsic integrated inputs and dictate mitochondrial output to meet the demands of the targeted tissue and the whole body.

The Yan lab studies an enzyme critical to this process. The sensing enzyme, called AMP-activated protein kinase, or AMPK, uses genome modulation and cellular signaling pathways to communicate energy demand to mitochondria, which, in turn, calibrate their ATP output to match the cell's changing energy demand.

"'At the right time to do the right thing' is the best description of Ryan's postdoc endeavor," Yan said. "Since he started at the Fralin Biomedical Research Institute, Ryan has capitalized on his expertise and fearlessly pursued fundamental questions regarding the role of mitoAMPK activation in exercise-induced adaptations and health benefits. Ryan has demonstrated an exceptionally strong commitment to biomedical research and has paved the way for great success in his academic career."

During rest periods, energy demands are relatively low, but during exercise or some other pathological stress, the requirements can increase dramatically and rapidly. In normal physiology, these stressors activate AMPK to ramp up ATP production. In many chronic diseases, this process is inhibited.

In Type 2 diabetes, for example, cells become resistant to insulin, the hormone responsible for aiding in glucose uptake. This creates a cellular environment in which normal energy-sensing mechanisms become overwhelmed and, ultimately, dysfunctional.

"Because of excess nutrition, skeletal muscle can become overexposed to glucose and therefore become desensitized to its anabolic effects," Montalvo said. "If your energy sensing mechanisms are impaired, your muscle mitochondria don't receive as clear a message about how to respond to a physiological or pathological stressor."

In 2021, the Yan lab published findings in the Proceedings of the National Academy of Sciences that revealed AMPK can be found not just throughout the cell, but specifically within the mitochondrial reticulum. This distinct AMPK pool, which the Yan lab named mitoAMPK after its location in the cell, may allow the enzyme to transmit clearer signals to mitochondria.

"The Yan lab was the first to characterize mitochondrial AMPK in skeletal muscle, but we have not identified why it localizes to the mitochondria," said Montalvo. The findings now serve as the foundation for a key question driving his research: "If we can increase the activity of mitochondrial AMPK, can we mitigate diabetes in skeletal muscle?"

Montalvo's project represents the first steps toward discovering whether enhancing mitochondrial energy sensing through targeted activation of mitoAMPK could provide a therapeutic pathway for diabetes treatment.