Dominican University of California
Effects of Heregulin on Muscle: A Biochemical and Histological Analysis
Abstract
dc:description.abstract<p>Duchenne Muscular Dystrophy, the most common inherited X-linked genetic disease affecting 1 in 5000 boys, results from a dysfunctional dystrophin protein encoded by the DMD gene. Dystrophin interacts with protein complexes linking the extracellular matrix to the cytoskeleton of muscle fibers. Without dystrophin functioning properly, sarcolemmal membrane stabilization is compromised during the mechanical rigors involved with muscle contraction leading to progressive muscular dystrophy. Heregulin/neuregulin-1 (HRG), a member of the epidermal growth factor family has been shown to induce neuromuscular junction (NMJ) gene expression in vitro and improve skeletal muscle function in dystrophic mice. However, it is unclear if the HRG effects were due to proliferation, cell survival, differentiation, or stimulation of NMJ formation to improve excitation-contractile coupling. To identify a mechanism of action, HRG effects were investigated through in vitro and in vivo experiments: characterization of downstream signaling, observation of the effects on acetylcholine receptor clustering in vitro, and observation of NMJ morphology in vivo. In this study we show through Western blots and electrochemiluminesence assays that AKT and ERK were activated by HRG, but downstream effects were not clear. HRG decreased laminin-induced AChR clusters in a dose dependent manner in vitro, resulting in the possible reorganization of AChRs. In vivo, HRG was found to partially restore NMJ formation and increase axonal and muscle integration in the NMJ. This study provides evidence that a mechanism of action for the positive effects of HRG on the dystrophic phenotype in mdx mice are due to a reorganization of AChRs and an improvement in NMJ formation, potentially improving excitation contraction coupling.</p>
Degree
thesis:*- Name thesis:degree_name
- Master of Science
- Level thesis:degree_level
- Master's Thesis
- Discipline thesis:degree_discipline
- Biological Sciences
- Year dc:date.available
- 2014
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Moss, Nicole Justine
- Contributors dc:contributor
-
- Paul Fitzpatrick, PhD
- Sean Bell, PhD
Subjects
dc:subject × 4Identifiers
dc:identifier.*- Repository record dc:identifier
- https://scholar.dominican.edu/masters-theses/50
- OAI identifier oai:identifier
- oai:scholar.dominican.edu:masters-theses-1053