Abstract TP079: Early periodical exercise promoting mitochondrial transport and Axonal Sprouting after cerebral ischemia via upregulation of irisin

Introduction: Early neurorehabilitation after cerebral ischemia can influence neural remodeling. Forced exercise initiated within 6 hours post-stroke enhances long-term recovery but aggravates acute injury, whereas early voluntary exercise is safer but less effective for long-term outcomes. We hypothesized that periodical exercise (PE), combining early voluntary exercise with later forced exercise, could maximize functional recovery while minimizing early injury. Irisin, a myokine cleaved from fibronectin type III domain-containing protein 5 (FNDC5) during physical activity, promotes neuroplasticity, synaptogenesis, and mitochondrial function, making it a potential mediator of exercise-induced neuroprotection. Methods: A total of 75 adult male Sprague-Dawley rats were divided into 5 groups: 1) sham, 2) stroke, 3) stroke with forced exercise (6h-28d, 30 min/day), 4) stroke with voluntary exercise (6h-28 d), 5) stroke with PE (voluntary, 6h-5d; forced 6-28d). Infarct volume and neurological deficit were evaluated acutely. Long-term functional outcomes were determined by grid walk, Rota-rod, adhesive tape touch, and Morris water maze. Levels of mRNA and proteins of neuroplasticity- and synaptogenesis-related markers were quantified by real-time PCR and Western blot. Electron microscopy (EM) examined mitochondrial ultrastructure at 28 days. Results: 1. Early forced exercise enlarged but PE reduced infarct volume. 2. PE yielded greater long-term functional recovery than voluntary or forced exercise alone. 3.PE increased brain irisin levels, reduces the expression of transporter protein (TSPO), a mitochondrial outer membrane protein upregulated during neuroinflammation, indicating suppressed inflammatory activation and improved mitochondrial stability; and inhibited axonal degeneration. 4. PE promoted synaptophysin, brain-derived neurotrophic factor and postsynaptic density protein-95 expression. 5. EM showed that PE effectively improved mitochondria ultrastructure by 43±3.5% and reduced mitochondria swelling by 36±2.1% after PE. Conclusions: Early PE is a promising rehabilitation strategy that mitigate axonal degeneration, promotes axonal sprouting, preserves mitochondrial integrity, and enhances neural plasticity via irisin upregulation and TSPO downregulation. This approach may inform clinical protocols to improve post-stroke recovery and reduce disability rates.