Alterations in systemic and skeletal muscle myostatin regulation are most prominent at disease onset and associate with muscle-related outcomes in idiopathic inflammatory myopathies

Recent findings indicate attenuated myostatin (MSTN) signalling in idiopathic inflammatory myopathies (IIM) and an inverse association between circulating MSTN and disease activity. The temporal and mechanistic relationship of these alterations to disease pathogenesis remains unclear. We therefore investigated systemic and skeletal muscle MSTN regulation in newly diagnosed patients at disease onset, after six months of therapy, and in chronic IIM. A total of 101 patients with IIM and 134 healthy controls (HC) were enrolled. Muscle biopsies were obtained from 59 newly diagnosed untreated or shortly treated patients, 19 patients after six months of therapy, 19 chronic IIM patients, and 21 HC. Serum samples and clinical data were collected during routine visits. Circulating MSTN, follistatin (FST), follistatin-like 3 (FSTL3) and activin A (ActA) were measured by ELISA. mRNA and protein expression of MSTN pathway components in muscle tissue were assessed by qPCR (TaqMan®) and immunoblotting. Associations of serum MSTN, FST, FSTL3 and ActA with clinical outcomes were analysed using linear mixed-effects models (LMM) and partial least squares regression during the first six months of therapy. Newly diagnosed IIM patients had significantly lower circulating MSTN and higher FST levels than chronic patients and HC, whereas ActA was elevated only in chronic disease. After normalization to body cell mass, MSTN remained reduced in newly diagnosed patients and increased after six months of therapy, while FST, ActA and FSTL3 did not change significantly. LMM analysis demonstrated strong associations of FSTL3 with systemic inflammation, disease activity and reduced physical and mental health scores, predominantly in female patients. In muscle tissue, newly diagnosed patients showed increased expression of MSTN pathway genes and proteins, including MSTN, SMAD2/3 and ubiquitin–proteasome components. Multivariate analyses integrating clinical, biochemical and molecular parameters identified a latent component linking MSTN pathway activation with muscle disease activity. Early IIM is characterized by dissociation between reduced circulating MSTN and activation of MSTN signalling in skeletal muscle, which diminishes with treatment and disease chronicity. Circulating FSTL3 is associated with systemic inflammation, disease activity and patient-reported outcomes, with pronounced associations in female patients. These findings highlight stage- and sex-dependent alterations of the MSTN regulatory network in IIM. 1. Myostatin pathway activation is most pronounced early in disease and attenuates with treatment and chronicity. 2. FSTL3 tracks systemic inflammation and patient-reported disease burden predominantly in female patients. 3. Integrated multivariate analysis links myostatin pathway activation with muscle disease activity.