New research provides a window into how, on a cellular level, exercise can improve muscle health and, ultimately, exercise capacity, which is "the best predictor of mortality in the general population."
"Whether muscle is healthy or not really determines whether the entire body is healthy or not," says lead researcher Prof. Zhen Yan, of the University of Virginia School of Medicine in Charlottesville.
"And exercise capacity, mainly determined by muscle size and function," he adds, "is the best predictor of mortality in the general population."
According to the new study, exercise improves muscle health by renewing its cellular powerhouse: the mitochondria. Mitochondria are crucial to the good functioning of our bodies, as well as to our overall health and longevity.
These tiny parts of the cell turn the food we eat into energy. Mitochondria transform proteins, fats, and sugars into the fuel that the body needs to live.
So, how does exercise affect the mitochondria in the muscles?
Exercise promotes mitophagy in mice
The answer given by the new study is through "mitophagy."
In the case of muscles, mitophagy contributes to keeping skeletal muscle healthy and strong. And to show how exercise induces mitophagy, Prof. Yan and team genetically modified mice to carry a gene that helps to report on the effects of physical activity.
This gene is called pMitoTimer. It makes mitochondria fluorescent, allowing the researchers to study mitophagy in vivo, after the mice engaged in 90 minutes of treadmill running.
Three to 12 hours after the running session, the researchers observed that mitochondria showed signs of stress. After 6 hours, they saw signs of mitophagy.
Prof. Yan explains the effect of exercise on mitochondria through an analogy that includes a vehicle inspection, the purpose of which is to remove defective cars from the streets.
"Aerobic exercise removes damaged mitochondria in skeletal muscle. If you do it repeatedly, you keep removing the damaged ones. You have a better muscle with better mitochondrial quality. We clean up the clunkers, now the city, the cell, is full of healthy, functional cars."
Prof. Zhen Yan
Chemical reaction in mitophagy identified
The researchers also identified the molecular mechanism behind the process. The treadmill workout seemed to activate a kinase called AMPK.
The researchers determined that, in a biochemical chain reaction, AMPK triggers another kinase called Ulk1.
Prof. Yan continues the vehicle inspection analogy, saying, "When [it's] turned on, Ulk1 activates other components in the cell to execute the removal of dysfunctional mitochondria."
"It's analogous to a 911 call where a tow truck removes the clunkers. However," he says, "we still do not know how these activities are coordinated."
To confirm their discovery - that Ulk1 plays a critical role in mitophagy - the team created a mouse model lacking the Ulk1 gene. These mice were also subjected to treadmill exercise, but the ensuing mitophagy was considerably inhibited.
"Mice that were unable to do mitophagy did not have the benefit of exercise," explains study co-author Joshua Drake, a postdoctoral fellow in Prof. Yan's laboratory.
"Even though, from an exercise standpoint, they still were able to run just as far as normal mice, they didn't benefit metabolically with training," he adds.
"These findings provide direct evidence of exercise-induced mitophagy and demonstrate the importance of Ampk-Ulk1 signaling in skeletal muscle," the authors conclude.