In these diabetic mice, LEX mice healed faster than CON mice; however, the HEX mice did not. Several studies3-5,11 have reported improved healing rates with moderate-intensity exercise. In addition, a recent study6 reported accelerated wound healing with low-intensity exercise in rats instead of mice. In this study, it was hypothesized that both LEX and HEX would accelerate healing, but that hypothesis was only supported in the LEX group. To the best of the authors’ knowledge, the present study is the first to show improvements related to low-intensity exercise but not for high-intensity exercise.
Low-intensity exercise in people with diabetes can decrease elevated blood glucose levels,10 among many other potential positive health benefits such as burning calories, decreasing total fat, adding muscle, and other beneficial effects. Since hyperglycemia and insulin resistance can delay healing,12,13 low-intensity exercise in these mice may have improved healing through decreased blood glucose and increased insulin sensitivity. In addition, because moderate exercise decreased some inflammatory cytokines in wounds of aged mice4 and may decrease systemic markers of inflammation in other populations,14,15 an improved cytokine profile in the wounds and/or blood of these diabetic mice may have allowed faster healing. Future studies should evaluate the impact of reduced hyperglycemia and reduced inflammation on improved healing resulting from exercise.
In contrast to the accelerated healing rate in the LEX mice, there was no significant change in the HEX mice. There are likely multiple reasons for this result. One possibility worthy of further exploration is that high-intensity exercise can be stressful to the mice and elicit a corticosterone response. Corticosterone (ie, cortisol in humans) can have a negative effect on wound healing rates,3,16 in addition to other negative effects on physiology, and may have slowed healing in HEX mice (however, this was not measured in this study). Indeed, there are many factors that can delay wound healing17,18 that may have mitigated the positive effects found in low-intensity and moderate-intensity exercise. The mechanisms behind exercise-induced changes to the complex processes involved in wound healing are not yet clear and make an exciting area of research.
High-intensity physical activity, including high-intensity interval training, has been associated with increased insulin sensitivity and better glucose tolerance.19-21 However, in the present study, insulin sensitivity was not measured and the high-intensity exercise was continuous, so it is unknown whether or not there was a beneficial effect to improving insulin resistance.
Similar results have been reported5 in young mice that were not diabetic. In that study,5 moderate exercise (70% of maximal capacity) improved wound healing, but 80% and 90% of maximal capacity were not as effective. Moderate-intensity exercise resulted in better wound closure and more mature granulation tissue, but high-intensity and strenuous-intensity exercise had delayed contraction.
When comparing the healing patterns between groups (Figure 3), the HEX pattern diverges early on from CON, with HEX wound sizes increasing for a couple days. This pattern also is seen in aged Balb-c mice.4 As mentioned earlier, a stress response mediated by corticosterone could lead to this delay. In addition, there is a difference in the LEX healing pattern compared with the CON on days 5 to 10. There are a number of possible explanations for this more rapid decrease in wound size in the LEX mice, including a change in the balance of pro-inflammatory versus anti-inflammatory cytokines in the wound environment.22 Another potential reason the investigators hope to explore further in future studies is the effect of exercise on macrophage function and polarization23,24 (ie, M1 to M2 shift). The role of exercise in altering markers of oxidative stress and angiogenesis also could provide valuable insight into these effects.