Muscle Stem Cell Lineage

Carnegie Institution Of Washington, D.C., Washington DC

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): A variety of mutations in humans cause muscular dystrophies. Among these genetic disorders, patients carrying non-sense mutations in the DMD gene or deletions that disrupt the reading frame present the most severe form of muscular dystrophies, i.e. Duchene's Muscular Dystrophy (DMD). DMD is an X-linked recessive disorder that affects ~ 1 in 3,500 boys. In the skeletal muscle, the primary DMD transcripts contain 79 exons and produce a protein of ~427 KD named Dystrophin. Dystrophin provides an essential linkage between cytoskeleton and extracellular matrix to maintain muscle integrity. Because internally truncated Dystrophin are partially functional, anti-sense oligonucleotide-directed skipping of mutated exon to restore DMD reading frame is in clinical trial to ameliorate the disease. A long-standing animal model for DMD is the mdx mouse, which carries a non-sense mutation in exon 23 of the homologous Dmd gene. A prominent feature in DMD patients and mdx mice are chronic inflammation associated with continuous muscle degeneration. IL4 and IL13 are anti-inflammatory peptide factors that also promote muscle regeneration. During the previous/current funding period, we found that IL4 or IL13 can induce muscle fibers to express truncated Dmd proteins, similar to those found by anti-sense oligonucleotide-directed exon skipping. We propose three aims to investigate the mechanisms which underlie IL4/13-inducible Dmd expression: Aim 1: Further characterizing the effects of IL4 and IL13 on mdx models. Aim 2: Examining the characteristics of IL4/ IL13-induced revertant fibers. Aim 3: Defining the cellular mechanism underlying IL4/IL13-induced Dmd reversion. Aim 4: Exploring the molecular mechanism underlying IL4/IL13-induced Dmd reversion. While our proposed research has exciting clinical implications to DMD patients, we focus on uncovering the mechanism underlying a novel biological phenomenon. Information gained from this study is essential for translating this study to clinical use.