Supplemental Digital Content is Available in the Text.Individuals with post–Coronavirus-19 condition report elevated pain, fatigue, psychological impact, and functional limitation similar, but less severe, than those with fibromyalgia and chronic fatigue syndrome.

Rigorous experimental design with transparent reporting in biomedical science reduces risk of bias and allows for scientists to judge the quality of the research. Basic factors of rigor such as blinding, randomization, power analysis, and inclusion of both sexes impact the reproducibility by reducing experimental bias. We designed a systematic study to analyze basic factors of rigor, inclusion of sex, and whether data were analyzed or disaggregated by sex over the past 10 years in the journal PAIN. Studies that included humans reported randomization in 81%, blinding in 48%, and the use of a power analysis calculation in 27% over the past 10 years. Studies that included mice reported randomization in 35%, blinding in 70%, and the use of a power analysis in 9%. Studies that included rats reported randomization in 38%, blinding in 63%, and the use of power analysis in 12%. This study also found that human studies consistently included both sexes over the past decade, but less than 20% of data were disaggregated or analyzed for sex differences. Although mouse and rat studies predominately used males only, there has been a slight increase in inclusion of both sexes over the past few years. Justification for single-sex studies was below 50% in both human and rodent data. In both human and animal studies, transparency in reporting of experimental design and inclusion of both sexes should be considered standard practice and will result in improved quality and reproducibility of published research.

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.

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