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The absence of the dystrophin protein in Duchenne muscular dystrophy (DMD) results in myofiber fragility and a plethora of downstream secondary pathologies. While a variety of experimental therapies are in development, achieving effective treatments for DMD remains exceptionally challenging, not least because the pathological consequences of dystrophin loss are incompletely understood. Here we have performed proteome profiling in tibialis anterior muscles from two murine DMD models (mdx and mdx52) at three ages (8, 16, and 80 weeks of age), all n=3. High-resolution isoelectric focusing liquid chromatography-tandem mass spectrometry (HiRIEF-LC-MS/MS) was used to quantify the expression of 4,974 proteins across all 27 samples. The two dystrophic models were found to be highly similar, whereas multiple proteins were differentially expressed relative to wild-type (C57BL/6) controls at each age. Furthermore, 1,795 proteins were differentially expressed when samples were pooled across ages and dystrophic strains. These included numerous proteins associated with the extracellular matrix and muscle function which have not been reported previously. Pathway analysis revealed multiple perturbed pathways and predicted upstream regulators which together are indicative of crosstalk between inflammatory, metabolic, and muscle growth pathways (e.g. TNF, INFγ, NF-κB, SIRT1, AMPK, PGC-1α, PPARs, ILK, and AKT/PI3K). Up-regulation of CAV3, MVP and PAK1 protein expression was validated in dystrophic muscle by Western blot. Furthermore, MVP was up-regulated during, but not required for, the differentiation of C2C12 myoblasts suggesting that this protein may affect muscle regeneration. This study provides novel insights into mutation-independent proteomic signatures characteristic of the dystrophic phenotype and its progression with aging.

Original publication

DOI

10.1074/mcp.RA120.002345

Type

Journal article

Journal

Mol Cell Proteomics

Publication Date

29/09/2020

Keywords

Duchenne muscular dystrophy, Gene Expression*, Neurodegenerative diseases*, Quantification, Tandem Mass Spectrometry, dystrophin, iTRAQ, mdx, mdx52, proteomics