Establishment of a Neurodegenerative Charcot Mouse Model

Abstract

Background: This study aimed to mimic the changes from Charcot neuropathic arthropathy in humans by examining the effects of exposing diet-induced obese (DIO) mice to neurotrauma through a regimented running protocol. Methods: Forty-eight male wild-type C57BL/6J mice were obtained at age 6 weeks and separated into 2 groups for diet assignment. After a 1-week acclimation period, half of the mice consumed a high-fat diet (60% fat by kcal) ad libitum to facilitate neuropathic diet-induced obesity whereas the other half were control mice and consumed an age-matched standard low-fat control diet (10% fat by kcal). At age 12 weeks, half of the animals from each group were subjected to a high-intensity inclined treadmill running protocol, which has been previously demonstrated to induce neurotrauma. Sensory testing and radiographic analyses were periodically performed. Histopathologic analyses were performed post killing. Results: DIO mice had significantly higher bodyweights, higher body fat percentages, and lower bone mineral density than wildtype control mice that were fed a normal diet throughout the experiment ( P < .001 for each). DIO mice displayed significantly reduced sensory function in week 1 ( P = .005) and this worsened over time, requiring 20.6% more force for paw withdrawal by week 10 ( P < .001). DIO mice that ran demonstrated greater midfoot subluxation and tarsal instability over all time points compared with normal-diet mice that ran ( P < .001). Histopathologic analyses revealed that DIO mice that ran demonstrated significant changes compared with controls that ran ( P < .001 for each parameter). Conclusion: Changes akin to the earliest changes observed in or before joint destruction identified in diabetic Charcot neuropathic arthropathy in humans were observed. Clinical Relevance: There is currently no standard of treatment for patients with Charcot neuropathic arthropathy. This study establishes a protocol for an animal model that can be used to study and compare interventions to treat this disease.