The impact of sex and physical activity on the local immune response to muscle pain

Abstract

Induction of muscle pain triggers a local immune response to produce pain and this mechanism may be sex and activity level dependent. The purpose of this study was to measure the immune system response in the muscle following induction of pain in sedentary and physically active mice. Muscle pain was produced via an activity-induced pain model using acidic saline combined with fatiguing muscle contractions. Prior to induction of muscle pain, mice (C57/BL6) were sedentary or physically active (24hr access to running wheel) for 8 weeks. The ipsilateral gastrocnemius was harvested 24hr after induction of muscle pain for RNA sequencing or flow cytometry. RNA sequencing revealed activation of several immune pathways in both sexes after induction of muscle pain, and these pathways were attenuated in physically active females. Uniquely in females, the antigen processing and presentation pathway with MHC II signaling was activated after induction of muscle pain; activation of this pathway was blocked by physical activity. Blockade of MHC II attenuated development of muscle hyperalgesia exclusively in females. Induction of muscle pain increased the number of macrophages and T-cells in the muscle in both sexes, measured by flow cytometry. In both sexes, the phenotype of macrophages shifted toward a pro-inflammatory state after induction of muscle pain in sedentary mice (M1+M1/2) but toward an anti-inflammatory state in physically active mice (M2+M0). Thus, induction of muscle pain activates the immune system with sex-specific differences in the transcriptome while physical activity attenuates immune response in females and alters macrophage phenotype in both sexes.

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice

“…Consistent with the role of hormones in modulating pain, we have shown that testosterone protects against the development of widespread pain in the activity-induced pain model [78], with orchiectomy producing widespread pain similar to females and testosterone producing unilateral pain similar to males. Further, we have shown female-specific mechanisms of pain in the activity-induced pain model where there was activation of the antigen processing and presentation pathway in the muscle, and blockade of MHC II attenuated development of muscle hyperalgesia [79]. Centrally, females but not males, also have greater serotonin transporter immunoreactivity in the nucleus raphe magnus [78].…”

A novel potential strategy for the treatment of inflammatory and neuropathic pain

“…10,16 Several reports suggested that CD44 activation in macrophages by HMWH can suppress the release of pronociceptive cytokines from tissue-infiltrating macrophages in rodents. 19,22 Furthermore, macrophages have been widely reported to be involved in the development of musculoskeletal pain 11,12,14,18 and have been specifically implicated in muscle pain development as a consequence of extracellular membrane hyaluronan disruption by hyaluronidase administration. 18 Local administration of HMWH has been shown to reduce the infiltration of immune cells in a rodent model of radicular pain postlaminectomy, 15 suggesting a potential use in surgical settings.…”