Effect of treadmill exercise on cutaneous wound healing in obese mice

Impaired wound healing induced by obesity is a major health care concern. Non-healing wounds account for greater than $25 billion in annual health care costs in the United States alone. Thus, therapies to speed healing are of major interest, and research into a number of therapeutic wound treatments is currently ongoing. Previous research indicates that short-term treadmill exercise training can speed wound healing rate in aged mice. As aged mice have impairments in wound healing similar to those seen in obese mice, we hypothesized that a similar exercise paradigm might speed healing rate in a high-fat diet-fed mouse model of obesity. We also examined whether exercise training would reduce wound inflammation in these mice, as exaggerated inflammatory responses are known to impair healing in obesity and as exercise training has been shown to reduce inflammation in a variety of tissues, including in wounds of aged mice. Therefore, we exercised mice for 3 days prior-to and 5 days post-exercise and measured wound area to day 10 post-wounding. Additionally, we measured non-wounded skin and wound site inflammation and growth factor expression through gene and protein expression analyses at baseline and at days 1, 3, and 5 post-wounding. Further parameters measured included exercise effects on adipose tissue inflammatory cytokine gene expression, on skin and wound macrophage number and phenotype, and on blood glucose kinetics. Exercise sped healing rate in obese mice, with the major effects happening early (within 5 days) post-wounding. Surprisingly, wound site inflammation was not affected by exercise, with no differences detected in gene or protein expression of inflammatory mediators or growth factors in non-wounded skin or in wounds at any time point after wounding. There was a moderate non-significant effect of exercise in reducing macrophage number in non-wounded skin, and there were no differences in fasting or stimulated blood glucose responses between exercised and sedentary obese mice. Interestingly, adipose tissue gene expression of several inflammatory cytokines were increased 2-3 fold in exercised mice, significantly so in several cases in the epididymal adipose depot. Additionally, epididymal adipose tissue expression of macrophage marker F4/80 was non-significantly increased, while in subcutaneous adipose tissue the expression of this marker was slightly decreased. Thus, while exercise was shown to speed healing in obese mice, the mechanism by which it acts is still unclear. Future research focusing on macrophage number and function in non-wounded skin of obese mice is necessary, as is research examining other potential mechanisms including exercise-enhanced wound contraction and exercise-induced alterations in skin microbiota. Finally, translational research is necessary to apply the findings here to a human population as it is not currently known whether exercise can speed healing in obese individuals in a clinical setting