Treadmill Exercise Can Modulate the Inflammatory Microenvironment and Promote Regeneration After Compressive Spinal Cord Injury in Female Mice.

Traumatic spinal cord injury (SCI) leads to severe sensorimotor impairments and reduced quality of life. Physical rehabilitation has emerged as a key therapeutic strategy to improve function and mitigate complications such as muscle atrophy and joint contractures, partly through modulation of the inflammatory microenvironment. This study investigated the effects of a structured exercise protocol on inflammation, neuroplasticity and sensorimotor recovery following compressive SCI in mice. Female C57BL/6 mice (8-12 weeks) were subjected to extradural spinal cord compression and divided into three groups: SHAM (laminectomy only), SCI (injury without treatment) and TMT (injury plus treadmill training). The TMT protocol began 7 days post-injury and continued until 56 days, with sessions performed three times per week. Functional assessments were conducted weekly, followed by electroneuromyography at 56 days and biochemical and morphological analyses after euthanasia. The TMT group demonstrated significantly improved locomotor performance and nociceptive response compared to the SCI group. Electroneuromyography revealed higher compound muscle action potential amplitudes in TMT and SHAM groups (p < 0.001). Additionally, TMT reduced muscle atrophy (p < 0.05) and increased neuromuscular junction density. Bladder wall thickness in TMT animals resembled SHAM and differed from SCI (p < 0.001), suggesting reduced inflammation. At the molecular level, TMT increased anti-inflammatory cytokines and reduced pro-inflammatory markers, alongside enhanced M2 microglial polarisation, decreased astrocyte reactivity and reduced apoptosis. Imaging analyses confirmed reduced lesion spread and fibrosis. These findings indicate that phase-adjusted exercise promotes functional recovery, neuromuscular plasticity and tissue preservation after SCI.