P.241 - Comparative high resolution proteomic analysis of dystrophic mouse models reveals a core dystrophic proteome and the impact of aging

Abstract

The most common form of childhood muscular dystrophy is Duchenne muscular dystrophy (DMD), which is a severe, X-linked muscle wasting disorder. The disease is caused by mutations in the DMD gene, leading to loss of the dystrophin protein which in turn causes progressive muscle degeneration and premature death. Various mouse models have been developed to study the disease, such as the commonly used mdx mouse, which has a nonsense mutation in exon 23, though this mutation is not characteristically present in humans. Another model is the mdx52 mouse, which has an exon 52 deletion in the mutation “hotspot” region of the DMD gene. To better understand the dystrophic phenotype and its progression with aging, we undertook for the first-time comparative proteomic analysis of both mdx and mdx52 models, using high-resolution isoelectric Focusing Liquid Chromatography-tandem Mass Spectrometry (HiRIEF-LC-MS/MS) with Tandem Mass Tag (TMT) isobaric labelling of tibialis anterior (TA) skeletal muscle to identify proteomic characteristics at 8, 16 and 80 weeks of age. Comparative proteomic analysis of mdx, mdx52 and C57BL/6 control mice identified 4,974 proteins in 27plex format and revealed a core set of proteomic changes reflective of the dystrophic phenotype. Proteomic analysis with age identified core proteomic features of normal muscle aging, overlap of these with progression of the dystrophic phenotype and features specific to the dystrophic phenotype with age. This study provides novel insight into specific proteomic changes characteristic of muscle aging and the relationship of these to dystrophic pathology over time.