If You Give a Mouse a Cookie: Quantification of Metabolic and Neurologic Changes in Murine Model for Charcot Arthropathy

Abstract

Category: Basic Sciences/Biologics; Diabetes Introduction/Purpose: Charcot arthropathy (Charcot) is a significant complication of diabetes mellitus thought to occur as a result of repetitive microtrauma to the insensate foot. We previously developed a murine model of diet-induced obese mice with peripheral neuropathy which underwent a high-intensity treadmill protocol designed to induce metabolic, neurologic, radiographic, and histopathologic features similar to Charcot in humans. Using this model, we aimed to further characterize the metabolic and sensory changes that occur in these diet-induced obese mice subjected to various high-intensity exercise protocols designed to induce repetitive microtrauma to the hind paws similar to Charcot. Methods: Forty-nine wild-type C57BL/6J mice were randomized to receive either a standard or high-fat diet and exposed to a high-intensity treadmill running protocol for various lengths of time as described in Figure 1A. Group 1 received a standard low-fat (10% kcal from fat) mouse diet and did not participate in the treadmill protocol. Groups 2, 3, 4, and 5 were fed a high-fat (60% kcal from fat) diet ad libidum to facilitate diet-induced obesity (DIO) and completed the treadmill protocol for various lengths of time. Initial body weights, DEXA scans, hind-paw Von-Frey filament sensory testing, and hot plate sensory testing following the previously published murine model were performed prior to the start of the running protocol and repeated at weeks 4, 8, 12, and 16. Plantar temperatures were measured initially and at 16 weeks. Paired-t-Test and one-way ANOVA were utilized to determine the significance of observed results. Results: Bodyweights are represented in Figure 1B. Plantar temperature was not significantly different between treadmill running groups at week 0 or 16 (Figure 1C). Hot plate testing demonstrated no significant difference in the number of responses between groups at week 0. By week 16, groups 3 and 5 demonstrated decreased hind-paw sensitivity to hot plate testing, suggestive of decreased sensation. Von Frey sensory testing also showed more force was required to induce a positive response, indicating decreased hind-paw sensation in high-fat diet groups (Figure 1D). By weeks 12 and 16, high-fat diet groups had significantly higher fasting blood glucose levels than group 1(Figure 1E). Additionally, high-fat diet groups demonstrated a significantly higher body fat percentage and lower bone mineral density (BMD) at weeks 0 and 16. Conclusion: Decreased sensitivity to hot plate and Von Frey testing demonstrate decreased sensation in the hind paws of DIO mice fed a high-fat diet. DIO mice also have significantly higher fasting blood glucose levels than mice fed a regular diet indicating impaired glucose tolerance. These metabolic and sensory changes suggest this is a reliable murine model of diabetic neuropathy. This model of diabetic neuropathy provides an avenue to study the radiographic and histologic changes that occur in these mice when exposed to repetitive exercise-induced microtrauma similar to Charcot arthropathy in humans.