Mechanisms of muscle afferent sensitization after ischemia

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Abstract: While great deal is understood about mechanisms of sensory transduction from the skin, relatively little is known about this process from the muscles. As peripheral injuries resulting from repetitive ischemic/reperfusion (I/R) are a major health issue that affects millions of people in the United States, this gap in knowledge precludes us from identifying specific therapies for muscle pain or altered cardiovascular responses to exercise in the context of ischemia. Peripheral I/R occurs in blood disorders such as sickle cell disease, and in cardiovascular disorders such as peripheral vascular disease. Males and females display different features of myalgia and exercise pressor reflexes (EPRs) under conditions of reduced peripheral perfusion. The major goal of this study is to determine the sex specific molecular mechanisms of muscle afferent sensitization that may underlie the transition from acute to chronic ischemic myalgia. Pilot data in murine models of repetitive I/R injury suggest that peripheral sensitization in males is regulated by increased DRG gene expression that is modulated by glial cell line-derived neurotrophic factor (GDNF) family receptor 1 (GFR1) in muscle nociceptors. In females, afferent sensitization, pain-related behaviors and altered EPRs after repeated I/R injury may be regulated by increased interleukin 1 receptor type 1 (IL1r1) dependent gene expression. We hypothesize that the prolonged effects of successive I/R injuries are mediated by GDNF related peripheral sensitization in males and IL1 induced sensitization in females. Aim 1 will determine if myofiber produced GDNF and DRG upregulation of GFR1, regulate the observed changes in muscle afferent response properties, pain-related behaviors and altered EPRs after dual I/R in males. We will use muscle fiber specific GDNF ablation or our novel in vivo siRNA-mediated knockdown of genes in single peripheral nerves in conjunction with our ex vivo muscle afferent recording preparations or assays of pain-like behaviors and EPRs. Aim 2 will utilize a similar approach except we will determine if macrophage produced IL1 or DRG upregulation of IL1r1, regulate the novel changes in female muscle afferents or behaviors after successive I/R. Finally, Aim 3 will use ex vivo recording and pain-related behavioral analyses to determine if expression differences in AU-rich element RNA-binding protein 1 (AUF1) or the ras family member, RAN, modulates the sex specific effects of successive I/R injuries between females versus males. Each of these aims will be complemented by analysis of DRG and muscle gene expression. The studies outlined here will also provide a novel direction in muscle neurobiology research that will go well beyond the incremental expansion of current reports. Results will enable us to identify unique sex dependent mechanisms associated with muscle afferent sensitization that underlie acute to chronic ischemic myalgia development after I/R injury. This may lead to the formulation of more appropriate treatments for musculoskeletal pain or altered EPRs associated with ischemia/ reperfusion that target the proper receptor(s), primary afferent subpopulation(s) or peripheral target tissues.