Scientists are investigating how exercise-triggered stress reshapes the cell’s energy systems, and whether those same mechanisms could eventually help counter metabolic disease.
Don’t like the gym? Exercise scientist Ryan Montalvo gets it. He still goes anyway, because the physical strain of exercise often leads to lasting health benefits.
Although workouts can feel intimidating, exercise triggers a biological reaction that helps cells prepare for future energy demands. This process, known as a hormetic response, occurs when a mild stressor stimulates beneficial adaptations. With support from an early-career research grant from the American College of Sports Medicine Research Endowment, Montalvo is studying whether this response to exercise stress could help counter noncommunicable diseases.
Montalvo works in Professor Zhen Yan’s lab at the Fralin Biomedical Research Institute at VTC. His research focuses on how the body adjusts to the stress caused by physical activity. By examining these changes, he hopes to better understand how exercise affects metabolic disorders such as 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 and the Cell’s Energy Supply
Mitochondria are structures inside cells that convert nutrients into adenosine triphosphate, or ATP. This molecule supplies the energy required for many biological activities, including muscle contraction during exercise and the chemical reactions that sustain normal 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.
Researchers in the Yan lab study a key enzyme involved in this energy sensing system. The enzyme, known as AMP-activated protein kinase, or AMPK, helps regulate how cells manage energy. It influences gene activity and cellular signaling pathways to inform mitochondria when more energy is needed. In response, mitochondria adjust their ATP production to match the cell’s current energy requirements.
“‘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.”
When Energy Sensing Breaks Down
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.
Reference: “Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy” by Joshua C. Drake, Rebecca J. Wilson, Rhianna C. Laker, Yuntian Guan, Hannah R. Spaulding, Anna S. Nichenko, Wenqing Shen, Huayu Shang, Maya V. Dorn, Kian Huang, Mei Zhang, Aloka B. Bandara, Matthew H. Brisendine, Jennifer A. Kashatus, Poonam R. Sharma, Alexander Young, Jitendra Gautam, Ruofan Cao, Horst Wallrabe, Paul A. Chang, Michael Wong, Eric M. Desjardins, Simon A. Hawley, George J. Christ, David F. Kashatus, Clint L. Miller, Matthew J. Wolf, Ammasi Periasamy, Gregory R. Steinberg, D. Grahame Hardie and Zhen Yan, 7 September 2021, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2025932118
Funding: American College of Sports Medicine
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