Sera from patients with dermatomyositis and antisynthetase syndrome mediate muscle weakness, impair mitochondrial respiration and induce local cytokine production in muscle tissue

Abstract

Objectives: Idiopathic inflammatory myopathies (IIM) are systemic autoimmune disorders characterized by skeletal muscle weakness and inflammatory cell infiltrates in muscle tissue. Although circulating systemic factors have been implicated in IIM, it is unclear to what extent such factors shape the muscle disease phenotype. Using a model that can isolate the effect of serum from other systemic influences, we aimed to investigate how serum from IIM affects skeletal muscle contractility, mitochondrial function and inflammatory signalling.

Methods: Isolated skeletal muscles (m. flexor digitorum brevis) from C57BL/6JRj mice were exposed for 24 h to sera from patients with IIM (n = 11) or healthy control sera. Muscle force was measured before and after serum exposure to assess weakness. Gene and protein expression was analysed to assess mitochondrial biogenesis and inflammatory cytokines. Mitochondrial respiration was assessed by high-resolution respirometry. Muscle transcriptomics was performed to identify signalling pathways perturbed by the IIM sera.

Results: Muscles exposed to sera from patients with IIM displayed significant contractile weakness and impaired mitochondrial respiratory capacity compared to muscles exposed to control sera (complex I; p = 0.0004, complex II; p = 0.0254, maximal electron transport chain activity; p = 0.0012). IIM sera induced upregulation of TNF-α (p = <0.0001) and IL1β (p = 0.0002) in the isolated muscles. Transcriptomics revealed significant enrichment in pathways linked to inflammation, mitochondrial metabolism and cytokine activity.

Conclusions: Serum from patients with IIM induced disease relevant phenotypes like those observed in muscle of patients, including weakness, local cytokine expression and mitochondrial dysfunction. These findings support the relevance of our model in recapitulating key features of IIM and further the mechanistic insights.

Keywords: ASyS; DM; IIM; Idiopathic inflammatory myopathies; Mitochondrial dysfunction; Serum; Skeletal muscle.