Exercise intensity and sex alter neurometabolic, transcriptional, and functional recovery following traumatic brain injury.

Physical exercise represents a potentially inexpensive, accessible, and optimizable rehabilitation approach to traumatic brain injury (TBI) recovery. However, little is known about the impact of post-injury exercise on the neurometabolic, transcriptional, and cognitive outcomes following a TBI. In the current study, we examined TBI outcomes in adolescent male and female mice following a controlled cortical impact (CCI) injury. Mice underwent a 10-day regimen of sedentary, low-, moderate-, or high-intensity treadmill exercise and were assessed for cognitive function, histopathology, mitochondrial function, and oxidative stress. Among male mice, low-moderate exercise improved cognitive recovery, and reduced cortical lesion volume and oxidative stress, whereas high-intensity exercise impaired both cognitive recovery and mitochondrial function. On the other hand, among female mice, exercise had an intermediate effect on cognitive recovery but significantly improved brain mitochondrial function. Moreover, single nuclei RNA sequencing of perilesional brain tissue revealed neuronal plasticity-related differential gene expression that was largely limited to the low-intensity exercise injured males. Taken together, these data build on previous reports of the neuroprotective capacity of exercise in a TBI model, and reveal that this rehabilitation strategy impacts neurometabolic, functional, and transcriptional outcome measures in an intensity- and sex-dependent manner.