Proteomics of muscle microdialysates identifies potential circulating biomarkers in Facioscapulohumeral muscular dystrophy

ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is caused by a complex epigenetic mechanism finally leading to the misexpression of DUX4, a transcription factor normally silenced in skeletal muscle. Detecting DUX4 in skeletal muscle and quantifying disease progression in FSHD is extremely challenging, thus increasing the need for other surrogate biomarkers. We applied a shotgun proteomic approach with two different setups to analyze the protein repertoire of interstitial fluids obtained from 20 FSHD patients’ muscles in different disease stages classified by Magnetic Resonance Imaging (MRI) and controls. Serum samples from the same subjects were also analyzed. A total of 1156 proteins were identified in the microdialysates by Data Independent Acquisition, 130 of which only found in muscles in active disease stage. Proteomic profiles of interstitial fluids were able to distinguish FSHD patients from controls. Among the upregulated proteins in muscles with active disease, two innate immunity mediators (S100-A8 and A9) and Dermcidin were detected with both proteomic approaches and selectively present in the sera of FSHD patients. Structural muscle proteins were downregulated, consistent with signs of early damage, as well as proteins of the plasminogen pathway. This suggests, together with upstream inhibition in FSHD samples of myogenic factors, defective muscle regeneration and increased fibrosis already in early/active disease. Conclusions: our MRI targeted exploratory approach provided insights on pathophysiological pathways activated in early disease, confirming that inflammatory response has a prominent role, together with impaired muscle regeneration. We also identified three proteins as tissue and possibly circulating prognostic biomarkers in FSHD.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Facioscapulohumeral Muscular Dystrophy 1

SUBMITTER: Victor Corasolla Carregari  

LAB HEAD: Giorgio Tasca

PROVIDER: PXD021838 | Pride | 2021-09-09

REPOSITORIES: pride