Pioglitazone modulates metabolic adaptation and peripheral nerve regeneration after injury

Peripheral nerves have an intrinsic capacity for regeneration after traumatic injury, with Schwann cells (SCs) playing a central role in orchestrating this complex process. Critical components of successful regeneration include SC reprogramming into repair SCs, debris removal and metabolic adaptations. Up to now, there are no pharmacological treatments available in the clinics to improve nerve regeneration. In this study, we investigated peroxisome proliferator-activated receptor gamma (PPARɣ) as a therapeutic target in the context of nerve regeneration, since we previously found this transcription factor to be involved in SC reprograming and metabolic adaptations. Therefore, we used a mouse model of sciatic nerve crush injury and applied the PPARɣ agonist pioglitazone (PIO) in two different treatment paradigms: (i) acutely after injury (0-5 days post injury) and (ii) delayed (5-21 days post injury), thereby addressing different phases of regeneration. Our findings revealed that PIO treatment immediately following nerve injury (first treatment paradigm) disrupted SC transition into the repair phenotype and diminished the physiological inflammatory response. As a consequence, axonal and myelin debris clearance was delayed, ultimately resulting in impaired axonal outgrowth and nerve regeneration. In the second treatment paradigm (PIO administration starting five days after injury) SCs had already acquired the repair phenotype and immune cell infiltration had taken place when PIO administration started. There, PIO promoted axonal regeneration, enhanced remyelination, and improved functional recovery. Importantly, PIO treatment increased mitochondrial content in neurons and SCs. In addition, delayed application of PIO induced lipid metabolism, glycolysis and ATP production in SCs, leading to the assumption that improved metabolic conditions mediate enhanced nerve regeneration in this treatment paradigm. These findings show that depending on the timing of PIO treatment, PPARɣ can serve as a potential therapeutic agent to improve nerve regeneration by promoting key metabolic adaptations.