Dissertation/Thesis Abstract

SMAD signaling drives heart and muscle dysfunction in muscular dystrophy
by Goldstein, Jeffery Adam, Ph.D., The University of Chicago, 2012, 149; 3526242
Abstract (Summary)

Mutations in dystrophin or its associated membrane proteins, the sarcoglycans lead to cardiomyopathy and muscular dystrophy in humans, mice, and flies. The dystrophin complex provides stability to the plasma membrane of striated muscle during muscle contraction. In the absence of the complex, cellular injury occurs, followed by an inappropriate response to that injury. In this thesis, I define a role for SMAD signaling, due to the activation of the TGFβ pathway, in this inappropriate response, as well as the assembly and trafficking of the sarcoglycan complex.

Increased SMAD signaling has been described in muscular dystrophy. I show that SMAD signaling is elevated in γ/δ-sarcoglycan ( Sgcd) mutant Drosophila and γ-sarcoglycan (Sgcg) mutant mice after muscle use. SMAD signaling is also induced in wild-type mice and flies after direct muscle injury, suggesting SMAD signaling is part of a stereotypical response to injury. I introduced a heterozygous null mutation of Medea, or its mouse homolog SMAD4 into sarcoglycan mutants to reduce SMAD signaling. In both model systems, reduction in SMAD signaling improved heart and skeletal muscle function. I treated Sgcg mice with an anti-TGFβ antibody in a short trial, and found mild improvement, suggesting a need for longer studies. Taken together, these data suggest that SMAD signaling is a therapeutic target in muscular dystrophy.

Targeted loss of γ- or δ-sarcoglycan results in a muscular dystrophy-like phenotype in mice, and deletion of the Drosophila homolog, γ/δ-sarcoglycan, results in a dystrophy-like phenotype in flies. To define functional domains in sarcoglycans using this homology, I generated mice that express Drosophila γ/δ-sarcoglycan, and fruit flies that express either mouse γ-sarcoglycan or mouse δ-sarcoglycan. Fly γ/δ-sarcoglycan localizes normally in wildtype murine muscle, and it requires the presence of murine δ-sarcoglycan for this localization suggesting the Drosophila sequence may function more like murine γ-sarcoglycan. Murine γ-sarcoglycan and murine δ-sarcoglycan localized normally in Drosophila muscle, indicating that these proteins contain sequences for proper trafficking. Together, these data provide insight on the requirements for assembly and trafficking of the sarcoglycan complex. Three supplemental videos are included.

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Indexing (document details)
Advisor: McNally, Elizabeth M.
Commitee: Ferguson, Edwin L., Moskowitz, Ivan I., Svensson, Eric C.
School: The University of Chicago
Department: Pathology
School Location: United States -- Illinois
Source: DAI-B 74/01(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Molecular biology, Pathology
Keywords: Drosophila, Heart failure, Mouse, Muscular dystrophy, Sarcoglycan complex, Tgf-beta signaling
Publication Number: 3526242
ISBN: 9781267601018
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