Treadmill training based on the overload principle promotes locomotor recovery in a mouse model of chronic spinal cord injury

Abstract

Rehabilitative treatment, including treadmill training, is considered an important strategy for restoring motor function after spinal cord injury (SCI). However, many unexplained problems persist regarding the appropriate rehabilitative method and the mechanism underlying the beneficial effects of rehabilitation. Moreover, only a few preclinical studies have been performed on rehabilitative interventions for chronic SCI, although most patients have chronic injuries. In fact, several preclinical studies reported that rehabilitative training was less effective when applied during the chronic phase than when applied sooner. While numerous studies have examined the effects of treadmill training during the subacute phase, the training conditions vary considerably among preclinical reports. Therefore, establishing a standard training protocol is essential for achieving beneficial rehabilitation effects at the chronic stage. Since the difficulty of applying an appropriate training load hinders training at constant speeds, it is important to adjust the training intensity in accordance with the exercise tolerance of an individual animal to provide further functional recovery benefits. Here, we created a novel quadrupedal treadmill training protocol based on the overload principle for mice with incomplete thoracic SCI. We subjected SCI model mice to rehabilitative training according to the protocol for two consecutive weeks starting at 42\u202fdays after injury. We examined the treadmill speeds at which the mice were able to run based on the severity of paresis and investigated the impact of the protocol on functional recovery. Assessment of running speed changes during the treadmill training period revealed faster treadmill speeds for mice with mild paresis than for those with severe paresis. The training parameters, including the speed and distance traveled, were positively correlated with the changes in motor function. These results suggest that the most suitable running speed during treadmill training differs according to the level of motor dysfunction and that running longer distances has a positive impact on motor functional recovery. Based on this established protocol, we compared functional and histological results between the chronic SCI groups with and without rehabilitation. The gait analyses showed significantly better functional improvement in the rehabilitation group than in the nonrehabilitation group. Histological analyses revealed that the BDNF- and VGLUT1-positive areas of lumbar enlargement were significantly increased in the rehabilitation group. These findings implied that rehabilitation promoted not only motor performance but also motor control, including forelimb-hindlimb coordination, even in chronic SCI, resulting in functional improvement by treadmill training alone. Therefore, rehabilitative training based on the overload principle appears to be one of the appropriate treatment options for incomplete thoracic SCI, and evidence of its efficacy exists in actual clinical settings.