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bioRxiv · 10.1101/2025.05.23.655872

12 weeks of voluntary wheel running restores glucagon sensitivity in middle-aged mice

Marx, T. J.·Bruner, K. R.·Ghimire, S.·Fletcher, T.·Stern, J. H.
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Abstract

Aerobic exercise training is a potent intervention for the treatment and prevention of age-related metabolic disease, which is characterized by both insulin and glucagon resistance. While insulin resistance is a key driver of metabolic disease in aging, glucagon signaling is equally critical in maintaining both glucose and lipid homeostasis, particularly during exercise. Previous studies have established the glucagon sensitizing effects of exercise training in younger animals. Most studies in rodents employ rigorous and carefully dosed forced exercise protocols. This forced exercise is a stressful paradigm. We implemented a voluntary wheel running (VWR) intervention to assess the effects of aging and exercise training on glucagon sensitivity. We initiated 12-weeks of VWR in young adult (6-month-old) and middle-aged (12-month-old) C57BL/6NCrl male mice. Glucagon sensitivity, as assessed by glucagon stimulated hyperglycemia, was decreased in middle-aged compared to young adult sedentary mice (P=0.046). While VWR did not affect glucose clearance, circulating insulin, glucagon, or insulin sensitivity, regardless of age, VWR improved glucagon responsivity only in middle-aged mice (P=0.031). VWR increased hepatic glycogen content and increased glucagon-stimulated glycogen depletion, regardless of age (P<0.01). Results from these studies suggest that exercise training can enhance liver glucagon action in aging mice without otherwise altering glucose homeostasis. New and NoteworthyFew studies have examined the impact of aging on glucagon sensitivity. Here we show that glucagon sensitivity declines from young adulthood to middle age. Yet, 12 weeks of voluntary wheel running, an exercise intervention without the stress of forced treadmill running or swimming, restores glucagon sensitivity in middle-aged male mice without otherwise altering glucose homeostasis.

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Marx, T. J., Bruner, K. R., Ghimire, S., Fletcher, T., Stern, J. H.. 2025-05-27. 12 weeks of voluntary wheel running restores glucagon sensitivity in middle-aged mice. https://doi.org/10.1101/2025.05.23.655872

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