Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is caused by a complex epigenetic mechanism finally leading to the misexpression of DUX4 in skeletal muscle. Detecting DUX4 and quantifying disease progression in FSHD is extremely challenging, thus increasing the need for surrogate biomarkers. We applied a shotgun proteomic approach with two different setups to analyze the protein repertoire of interstitial fluids obtained from 20 muscles in different disease stages classified by magnetic resonance imaging (MRI) and serum samples from 10 FSHD patients. 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 were able to distinguish FSHD patients from controls. Two innate immunity mediators (S100-A8 and A9) and Dermcidin were upregulated in muscles with active disease and selectively present in the sera of FSHD patients. Structural muscle and plasminogen pathway proteins were downregulated. Together with the upstream inhibition of myogenic factors, this suggests defective muscle regeneration and increased fibrosis in early/active FSHD. Our MRI targeted exploratory approach confirmed that inflammatory response has a prominent role, together with impaired muscle regeneration, before clear muscle wasting occurs. We also identified three proteins as tissue and possibly circulating biomarkers in FSHD.
Highlights
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies and is characterized by initial weakness of the facial, shoulder and upper arm muscles potentially progressing to affect almost all skeletal muscles [1].In its most prevalent form, it is associated with the deletion of a subset of D4Z4 microsatellite repeats in the subtelomeric region of chromosome 4q which allows, in the presence of a polyadenylation signal sequence, the stable expression of the DUX4 retrogene
We found that most of the proteins in peblood were present in the microdialysates, confirming their secretory origin from ripheral blood were present in the microdialysates, confirming theirand secretory origin skeletal muscle, which represents the most abundant tissue of our body, in accordance from skeletal muscle, which represents the most abundant tissue of our body, and in acwith a recent proteomic profiling of DUX4 overexpressing cells that showed an upregulation cordance with a recent proteomic profiling of
We report that S100-A8, S100-A9, Dermcidin and Insulin-growth factor-binding 4 were significantly upregulated in short tau inversion recovery (STIR)+ muscles compared with STIR, together with Prostaglandin-H2 D-isomerase
Summary
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies and is characterized by initial weakness of the facial, shoulder and upper arm muscles potentially progressing to affect almost all skeletal muscles [1].In its most prevalent form, it is associated with the deletion of a subset of D4Z4 microsatellite repeats in the subtelomeric region of chromosome 4q which allows, in the presence of a polyadenylation signal sequence, the stable expression of the DUX4 (double homeobox 4) retrogene. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies and is characterized by initial weakness of the facial, shoulder and upper arm muscles potentially progressing to affect almost all skeletal muscles [1]. DUX4 protein and transcript levels cannot be measured in muscle tissue from FSHD patients [2], making the use of DUX4 as a biomarker unviable. The low level of its expression is in any case sufficient to determine several downstream molecular events, most notably including the activation of genes involved in germline and early stem cell development, innate immunity, and cancer testis antigens [3]. Studies investigating the protein levels of these downstream targets in skeletal muscle and serum of FSHD patients are currently lacking.
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