Impaired proteostasis and unfolded-protein response activation in skeletal muscle of systemic sclerosis patient

Abstract-Text (inkl. Referenzen)

Introduction Systemic Sclerosis (SSc) is a rare autoimmune disease characterized by obliterative vasculopathy, accumulation of ECM proteins, fibrosis and inflammation, as well as specific autoantibodies. Almost any organ may be affected, leading to potentially life-threatening complications such as interstitial lung disease, gastrointestinal failure or pulmonary arterial hypertension. The exact molecular mechanisms contributing to the manifestation of SSc are still incompletely understood, but ER-stress and UPR-activation have been demonstrated in patient-derived PBMCs.

Methods Here we aim to unravel the impact of perturbed protein homeostasis in SSc-associated myositis by unbiased proteomic profiling of SSc skeletal muscle tissue. Confirmational studies are based on immunostaining and qPCR.

Results Proteomics on SSc muscles allowed quantification of 2290 proteins with 216 of them being significantly dysregulated: 14 of these proteins are directly involved in ER-homeostasis and UPR activation. Additional 15 proteins belong to proteolysis. Histological validation of these analyses confirmed these findings and showed up-regulation of UPR-branches, chaperones and aggregation markers.

Summary We here add altered protein response with strong up-regulation of UPR-mediated pathways on gene, as well as protein level in skeletal muscle of SSc patients to the pathophysiological spectrum of the disease and thus expand the current understanding of the underlying disease mechanism.