In her latest study, Rachel Perry, PhD, of Yale School of Medicine, reveals one of the clearest mechanisms to date behind a question patients often ask: Why
The answer, they found, is that working muscles effectively outcompete tumors for the glucose supply. Because muscle contraction increases glucose uptake, exercise shifts metabolism, causing tumors to receive less of the fuel they need to grow.
Exercise has both long and short term effects on glucose, 1. upregulates insulin receptor production, 2. fires off receptors on muscles to haul the glucose out of the blood and into the muscles for immediate use, and for storage as glycogen (stacks of glucose). And there’s a lot more being looked at in this paper, and for that matter more going on in exercise effects on tumors than just glucose regulation, tho’ it is an important piece.
Significance
It is well established from both preclinical and clinical studies that exercise protects against tumor growth and progression. However, the biomarkers of this beneficial effect are not well delineated. Here, we demonstrate using stable isotope tracer methodology and unbiased metabolomics analyses that aerobic exercise induces glucose repartitioning in rodents with breast cancer and melanoma. We further demonstrate that fitness—which can be measured along a continuum, beyond the binary “exercise/no exercise” paradigm that may not translate well to humans in practice—is a key predictor of tumor metabolism. These data highlight the importance of a nuanced, systemic view of the metabolic effects of exercise in cancer.
Abstract
Higher exercise capacity and regular exercise training improve cancer prognosis at all stages of disease. However, the metabolic adaptations to aerobic exercise training that mediate tumor–host interactions are poorly understood. Here, we demonstrate that voluntary wheel running slows tumor growth and repartitions glucose uptake and oxidation to skeletal and cardiac muscle and away from breast and melanoma tumors in mice. Further, prehabilitation induces repartitioning of glucose metabolism in obese mice: Uptake and oxidation of glucose are enhanced in skeletal and cardiac muscle, and reduced in tumors. These increases in muscle glucose metabolism and reductions in tumor glucose metabolism, correlated with slower tumor progression. Using [U-13C6] glucose infusion, we show that exercise increases the fractional contribution of glucose to oxidative metabolism in muscle while reducing it in tumors, suggesting that aerobic exercise shifts systemic glucose metabolism away from the tumor microenvironment and toward metabolically active tissues. Transcriptional analysis revealed downregulation of mTOR signaling in tumors from exercised mice. Collectively, our findings suggest that voluntary exercise may suppress tumor progression by enhancing host tissue glucose oxidation and limiting tumor glucose availability, supporting a model in which exercise-induced metabolic competition constrains tumor energetics.
Nailed it. Down to the use of the word “fuel”.
Exercise has both long and short term effects on glucose, 1. upregulates insulin receptor production, 2. fires off receptors on muscles to haul the glucose out of the blood and into the muscles for immediate use, and for storage as glycogen (stacks of glucose). And there’s a lot more being looked at in this paper, and for that matter more going on in exercise effects on tumors than just glucose regulation, tho’ it is an important piece.
Precancer exercise capacity and metabolism during tumor development coordinate the skeletal muscle–tumor metabolic competition https://www.pnas.org/doi/10.1073/pnas.2508707122
Significance It is well established from both preclinical and clinical studies that exercise protects against tumor growth and progression. However, the biomarkers of this beneficial effect are not well delineated. Here, we demonstrate using stable isotope tracer methodology and unbiased metabolomics analyses that aerobic exercise induces glucose repartitioning in rodents with breast cancer and melanoma. We further demonstrate that fitness—which can be measured along a continuum, beyond the binary “exercise/no exercise” paradigm that may not translate well to humans in practice—is a key predictor of tumor metabolism. These data highlight the importance of a nuanced, systemic view of the metabolic effects of exercise in cancer. Abstract Higher exercise capacity and regular exercise training improve cancer prognosis at all stages of disease. However, the metabolic adaptations to aerobic exercise training that mediate tumor–host interactions are poorly understood. Here, we demonstrate that voluntary wheel running slows tumor growth and repartitions glucose uptake and oxidation to skeletal and cardiac muscle and away from breast and melanoma tumors in mice. Further, prehabilitation induces repartitioning of glucose metabolism in obese mice: Uptake and oxidation of glucose are enhanced in skeletal and cardiac muscle, and reduced in tumors. These increases in muscle glucose metabolism and reductions in tumor glucose metabolism, correlated with slower tumor progression. Using [U-13C6] glucose infusion, we show that exercise increases the fractional contribution of glucose to oxidative metabolism in muscle while reducing it in tumors, suggesting that aerobic exercise shifts systemic glucose metabolism away from the tumor microenvironment and toward metabolically active tissues. Transcriptional analysis revealed downregulation of mTOR signaling in tumors from exercised mice. Collectively, our findings suggest that voluntary exercise may suppress tumor progression by enhancing host tissue glucose oxidation and limiting tumor glucose availability, supporting a model in which exercise-induced metabolic competition constrains tumor energetics.