Sex Specific Role of RNA-binding Protein, AUF1, in the Evolution of Acute to Chronic Pain after Repetitive Ischemia with Reperfusion Injury

Abstract

Myalgia is experienced worldwide more than any other type of pain. Prevention and treatment strategies are limited in the ability to prevent acute muscle pain from developing into chronic pain. One source of disease-based myalgia is repetitive ischemia with reperfusion (IR) injury. IR occurs in many disorders such as fibromyalgia or complex regional pain syndrome, which is reported significantly more in females compared to males. Our previous preclinical work suggested sex specific peripheral mechanisms of IR-related hypersensitivity after repetitive IR injury. One factor possibly underlying this phenomenon is a female specific expression pattern of phosphorylated AU-rich element RNA binding protein 1 (AUF1) in the dorsal root ganglion (DRG) which can differentially alter pain-related gene expression. To test if AUF1 regulated sex specific ischemic myalgia development, we performed a brachial artery occlusion followed by reperfusion on both sexes at p21-p28, followed by a second IR 7 days later to develop prolonged pain-like behaviors. We assessed spontaneous paw guarding and mechanical hypersensitivity to muscle squeezing in male and female mice with nerve-specific siRNA-mediated knockdown or AAV-mediated overexpression of AUF1 and compared them to controls. Affected muscles and/or DRGs were taken for immunohistochemistry, PCR or western blot analysis. We found that knockdown of AUF1 inhibited spontaneous paw guarding only in female mice. This corresponded with a specific inhibition of female related gene expression in the DRGs but did not alter male gene expression patterns. AAV-mediated overexpression of AUF1 in males however was found to produce prolonged paw guarding responses after repeated IR similar to that observed in females with dual IR. This study indicates that there are distinct receptor differences in relation to the development of acute to chronic pain between sexes. Results could provide evidence for development of sex specific treatment strategies for patients with IR-related pain. Grant support from R01NS113965 and R01NS105715.