Exercise reshapes inflammation at the cellular level, and understanding exactly how could unlock therapies for chronic disease and age-related frailty.
At the Langston Lab at Yale School of Medicine, researchers focus on understanding how special populations of cells in tissues sense exercise and shape its benefits within and across organs.
“We’re trying to understand the multicellular nature of tissue responses to stress, including stress from exercise,” says Kent Langston, PhD, assistant professor of pathology and the lab’s principal investigator. Langston’s latest study, published in Nature Immunology, builds on the lab’s previous work demonstrating that muscle inflammation is not merely part of the stress response to exercise, but a regulator of how the body adapts to exercise.
The new study reveals that muscle inflammation after exercise and injury is caused by activation of Piezo1, a protein found on stromal cells in muscle. Piezo1 functions as a molecular "force sensor" in the human body, converting physical stimuli—such as pressure, stretching, or fluid flow—into electrical and chemical signals within cells. Muscle inflammation doesn’t always happen after exercise. Langston’s previous work has found that there is a threshold for exercise load—intensity times duration—that must be crossed for muscle inflammation to occur.
Langston, the study’s first author, began the work with Harvard colleagues before coming to Yale last year. He notes that the skeletal muscle’s central role in producing movement and regulating metabolism makes it a site where inflammatory reactions to stress must be precisely balanced to avoid long-lasting problems with muscle function. Exercise, injury, and aging are common forms of stress associated with inflammation; yet the specific inducers and sensors driving such inflammation remain poorly characterized.
Studies on exercise show that, in addition to muscle fibers, the other cells constituting muscle tissue (i.e., non-parenchymal cells) also respond to exercise. The new study from Langston and colleagues reveals that mechanical stress associated with changes in muscle stiffness, which Piezo1 senses, is a key signal calling these non-parenchymal cells into action. Their work shows that stromal cells need to sense such mechanical changes to trigger inflammation and muscle repair responses at the right time after exercise and injury. This process is also linked to inflammation in aging muscles.
The findings highlight that Piezo1 and its sensing of changes in tissue stiffness are a fundamental mechanism of how stress initiates an immune response in skeletal muscle.
“We’re trying to figure out if we can pinpoint the signals that cause inflammation during exercise—and we find that these same signals are present in conditions like aging,” Langston says. “Can we then therapeutically target these signals to modulate the immune system favorably?”
The lab also wants to understand how the immune system communicates with muscle fibers and regulates their activities, with the goal of developing exercise-inspired therapies.
“What are the signals that lead to a response from the immune system, and when you get a response, how does that affect muscle function?" Langston asks. “We want to understand the basic immunobiology of muscle and produce therapies that can be done in addition to exercise. Because, as we know, there’s nothing that replaces exercise. It’s the best thing you can do to counteract aging.”