How the body responds to exercise at the cellular level
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Researchers have long been intrigued by the possibility that exercise causes various cells in our bodies to produce molecules that benefit human health, says Jonathan Long, an assistant professor of pathology at Stanford University.
If these molecules, which are sometimes called exercise factors or exerkines, can be identified and exploited for pharmacological purposes, the theory goes, they could reduce the incidence of certain health problems such as obesity, heart disease and diabetes. as well as improve athletic performance. .
But that goal has remained elusive in large part because it has been impossible to isolate exercise from blood, says Long. “If you analyze whole blood, you can only see the most abundant substances and everything else is invisible.”
Now, however, Long and his team have developed a new technique that can look much deeper into the blood to identify molecules secreted by cells. The technique also reveals which cell types produce which molecules, key information for better understanding the role exercise plays in improving health.
And Long’s new method has now produced a cellular metabolism article demonstrating the myriad ways exercise changes protein secretion by 21 different cell types in mice. The work also held some surprises.
First, the sheer number of proteins whose presence in the blood changed in response to exercise was greater than expected. In fact, the team found nearly 200 different exercise factors whose expression was up-regulated or down-regulated by the 21 cell types. “This means that the effects of physical activity are widespread in many tissues and organ systems,” says Long. “We’re just starting to understand that complexity.”
Second, the cells most responsive to exercise were a poorly understood cell type named after a particular protein receptor (Pdgfra) and found in many different tissues and organs. In fact, the usual suspects like muscle, bone and liver cells all had only moderate responses by comparison, Long says. “If we really want to understand the response to exercise, we can’t just focus on muscles and bones and the other tissues we associate with exercise,” she says. “We have to look much more broadly.”
The team was also surprised to find that liver cells, and liver cells alone, secrete different members of the carboxylesterase family of proteins after exercise. Researchers had previously focused on the functions of these proteins within a cell and demonstrated that they were beneficial for metabolic health, but hadn’t observed a possible role in blood flow.
To better understand their role, Long’s team engineered mice that secreted high levels of protein carboxylesterases from their livers without exercise. And, it turned out, these mice resisted weight gain on a high-fat diet and showed better endurance on a treadmill. “These carboxylesterases are sufficient to impart some of the metabolic benefits of exercise without the animals exercising themselves,” says Long.
The study raises many questions for follow-up. What role do Pdgfra cells play in different tissues and why do these cells respond to exercise? Just as carboxylesterases show metabolic benefit, could other exerchines have important anti-inflammatory or other beneficial effects on the bones, heart, immune system, and brain? In humans, do blood-transported carboxylesterase levels change in response to exercise as they do in mice?
From a basic science perspective, Long hopes this work will improve our understanding of cell-to-cell communication. But from a view of 30,000 feet, there’s another reason to do these kinds of laborious research studies: the unfulfilled promise of “exercise as medicine.”
We know that exercise has a therapeutic effect in many of the most chronic and debilitating diseases, but exercise is still not like medicine, Long says. This is because most medicines consist of well-defined molecules with well-defined mechanisms of action, pharmacokinetics and pharmacodynamics, and adverse effects. Conversely, neither of those things are well defined for exercise, he says. “Long-term we want to understand the molecules and cells associated with exercise in high resolution so that exercise as medicine can become a reality.”
Wei Wei et al., Cell-type-specific and organism-level secretome mapping of exercise training in mice, cellular metabolism (2023). DOI: 10.1016/j.cmet.2023.04.011
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