Compelling evidence supports the health benefits of physical exercise on the immune system, possibly through the molecules secreted by the skeletal muscles known as myokines. Herein, we assessed the impact of exercise interventions on plasma Heat shock protein 90 (Hsp90) levels in 27 patients with idiopathic inflammatory myopathies (IIM) compared with 23 IIM patients treated with standard-of-care immunosuppressive therapy only, and in 18 healthy subjects undergoing strenuous eccentric exercise, and their associations with the traditional serum markers of muscle damage and inflammation. In contrast to IIM patients treated with pharmacotherapy only, in whom we demonstrated a significant decrease in Hsp90 over 24 weeks, the 24-week exercise program resulted in a stabilization of Hsp90 levels. These changes in Hsp90 levels were associated with changes in several inflammatory cytokines/chemokines involved in the pathogenesis of IIM or muscle regeneration in general. Strenuous eccentric exercise in healthy volunteers induced a brief increase in Hsp90 levels with a subsequent return to baseline levels at 14 days after the exercise, with less pronounced correlations to systemic inflammation. In this study, we identified Hsp90 as a potential myokine and mediator for exercise-induced immune response and as a potential biomarker predicting improvement after physiotherapy in muscle endurance in IIM.

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Objectives Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with systemic sclerosis (SSc). It is associated with skin and lung involvement and disease activity. Contrary, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 monoclonal antibody (mAb, 6B12) in the treatment of preestablished experimental dermal fibrosis. Methods The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated (p)Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNASeq). Results Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count, and collagen content. These antifibrotic effects were mediated by the downregulation of transforming growth factor-β/Smad signaling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of interleukin-1α, eotaxin, CCL2, and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc. Conclusion Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc.