June 11, 2020—The immune system is well known for its ability to fight foreign pathogens. But does it also influence other important functions, like muscle fitness? New research led by Harvard T.H. Chan School of Public Health provides new insights into how the immune and metabolic systems work hand-in-hand to help satisfy our bodies’ heightened demand for energy during endurance exercise.
The study, published in Science on May 1, 2020, showed that a protein called Interleukin-13 (IL-13) released by immune cells directs the metabolic programing in muscle tissue to provide sustained energy during endurance training. This vital adaptive process is activated in response to exercise and maintained by endurance training.
“Scientists have known for more than 50 years that small circulating proteins mediate some of the metabolic effects of exercise,” said research fellow Nelson Knudsen, first author of the study. “Prior work has mostly focused on factors produced by muscle. Our study is one of the first to suggest that signaling from immune cells in the muscle are really important for endurance training.”
During exercise, the body must quickly ramp up fuel supply to hardworking muscles. There are two types of energy systems: anaerobic and aerobic. Anaerobic metabolism processes sugar stored in the form of glycogen to produce fuel molecules called ATP. This process does not require oxygen and can generate short bursts of energy during intense exercise.
Aerobic metabolism, on the other hand, uses oxygen to generate ATP fuel from carbohydrates and fat. This slow-burn process kicks in during longer-duration exercise. Scientists have long suspected that immune cells residing within muscle tissue help mediate these essential metabolic processes – but the exact mechanism of this coordination was not known.
The study, conducted in the laboratory of professor Chih-Hao Lee in the Department of Molecular Metabolism, found that endurance-trained men and women had noticeably higher levels of the immune signaling protein IL-13 circulating in their blood. Endurance-trained laboratory mice that spent hours on the treadmill also showed high levels of IL-13. But genetically-modified laboratory mice that could not produce IL-13, failed to ramp up their metabolic response to endurance training, suggesting that IL-13 protein plays a critical role.
Further studies in mice showed that IL-13 acts as signaling protein to launch a series of metabolic events that further facilitate fat-burn and endurance capacity in muscle tissue. The authors conclude that the body relies on IL-13 signaling to prime the muscle for aerobic metabolism in response to endurance exercise.
Endurance training has many known health benefits. These findings demonstrate how immune signaling works in coordination with the metabolic pathway to support the body’s needs during prolonged physical activity.
“Our work highlights the important role that the immune system plays in mediating the adaptation of muscle to regular exercise,” Lee said. “Whereas it’s well established that unresolved inflammation causes human diseases, our study emphasizes the interplay of immunity and metabolism in the maintenance of physiological functions of healthy individuals.”
Other Harvard Chan School researchers who contributed to the study include Kristopher Stanya, Alexander Hyde, Mayer Chalom,Ryan Alexander, Yae-Huei Liou, Kyle Starost, Matthew Gangl, David Jacobi, Sihao Liu, Diogo Fonseca-Pereira, Jun Li, Frank Hu, and Wendy Garrett. Colleagues from University of Texas McGovern Medical School, Emory University School of Medicine, and the University of Georgia also contributed to the study.
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