Journal
MOLECULAR & CELLULAR PROTEOMICS
Volume 19, Issue 12, Pages -Publisher
ELSEVIER
DOI: 10.1074/mcp.RA120.002345
Keywords
tandem mass spectrometry; iTRAQ; neurodegenerative diseases; quantification; gene expression; Duchenne muscular dystrophy; dystrophin; mdx; mdx52; proteomics
Categories
Funding
- Muscular Dystrophy UK (MDUK)
- UK Medical Research Council (MRC)
- Japan Society for the Promotion of Science [18K07544, 28-6]
- Women and Children's Health Research Institute
- Friends of Garrett Cumming Research and Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair
- Swedish Research Council
- Swedish Cancer Society
- Swedish Foundation for Strategic Research
- Stockholm County Council (ALF)
- Cancer Society in Stockholm
- Swedish Foundation for Strategic Research (SSF-IRC)
- Grants-in-Aid for Scientific Research [18K07544] Funding Source: KAKEN
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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. Although 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 MS (HiRIEF-LC-MS/MS) was used to quantify the expression of 4974 proteins across all 27 samples. The two dystrophic models were found to be highly similar, whereas multiple proteins were differentially expressed relative to WT (C57BL/6) controls at each age. Furthermore, 1795 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 that have not been reported previously. Pathway analysis revealed multiple perturbed pathways and predicted upstream regulators, which together are indicative of cross-talk between inflammatory, metabolic, and muscle growth pathways (e.g. TNF, INF gamma, NF-kappa B, SIRT1, AMPK, PGC-1 alpha, PPARs, ILK, and AKT/PI3K). Upregulation of CAV3, MVP and PAK1 protein expression was validated in dystrophic muscle by Western blot. Furthermore, MVP was upregulated 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. In this study we report the highest resolution proteomics analysis performed in dystrophic muscle to date. The use of two mouse models of Duchenne muscular dystrophy, at three different ages, has enabled the identification of mutation-independent protein signatures associated with dystrophic muscle, and the progression of disease pathology.
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