ProBDNF Upregulation in Murine Hind Limb Ischemia Reperfusion Injury: A Driver of Inflammation

SIMPLE SUMMARY: Ischemia reperfusion injury in skeletal muscle is common, yet the underlying mechanisms are not well understood. Additionally, the role of brain-derived neurotrophic factor and its precursor in skeletal muscle have not been determined. To address this, the present study aimed to investigate the role of pro-brain-derived neurotrophic factor in ischemia reperfusion injury of the hind limb. It was shown that pro-brain-derived neurotrophic factor is significantly upregulated in skeletal muscle following injury, and that in the absence of skeletal muscle pro-brain-derived-neurotrophic factor signaling, the inflammatory response was significantly blunted. The overall conclusion is that pro-brain-derived neurotrophic factor is essential to the inflammatory response following ischemia reperfusion injury. ABSTRACT: Brain-derived neurotropic factor (BDNF) has been shown to be expressed in many nonneuronal tissues including skeletal muscle. Skeletal muscle BDNF has been studied regarding its function in metabolism and exercise; however, less is known about its role in skeletal muscle injury. The precursor to BDNF, proBDNF, has an unknown role in skeletal muscle. The levels of proBDNF, mature BDNF, and their receptors were compared in the skeletal muscle and brain tissues of C57BL/6J mice. Tourniquet-induced hind limb ischemia-reperfusion injury was used to assess the function of skeletal muscle-derived proBDNF in skeletal muscle injury. Skeletal muscle-specific knockout of BDNF and pharmacological inhibition of p75NTR, the proBDNF receptor, were used to determine the role of proBDNF–p75NTR signaling. We show for the first time that proBDNF is the predominantly expressed form of BDNF in skeletal muscle and that proBDNF is significantly upregulated in skeletal muscle following hind limb ischemia-reperfusion injury. Skeletal muscle-specific knockout of BDNF blunted the inflammatory response in the injured tissue and appears to be mediated by the proBDNF–p75NTR pathway, as shown by the pharmacological inhibition of p75NTR. These findings suggest that skeletal muscle proBDNF plays a critical role in driving the inflammatory response following skeletal muscle injury.