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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.
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© 2022 Published by Elsevier Inc.