Date of Award

8-2012

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Clarissa Henry

Second Committee Member

Dorothy E. Croall

Third Committee Member

Leif Oxburgh

Abstract

A variety of diseases, both inherited and acquired, affect muscle tissues in humans. The anchoring of muscle fibers to their surrounding environment is critical for muscle homeostasis. Muscle fibers attach to their microenvironment through cell-matrix adhesion complexes. These anchoring complexes are placed under repeated stress during muscle contraction. Genetic mutations in these complexes weaken the attachment between muscle fibers and their microenvironment, making fibers more susceptible to damage and death. This increased fiber degeneration eventually leads to progressive muscle wasting diseases, known as congenital muscular dystrophies. Although clinical trials are ongoing, there is presently no way to cure the loss of muscle structure and function associated with congenital muscular dystrophies.
Animal models of human diseases are used to gain insights into mechanisms of disease pathogenesis and to screen for potential therapeutic compounds. The zebrafish CELL-MATRIX ADHESION IN MUSCLE model system, well-known for its use in developmental biological studies, is rapidly becoming widely-accepted as a useful model for biomedical research. We utilized zebrafish embryos to study the initial morphogenesis of substructures in the muscle microenvironment and the initial stable cell-matrix adhesions formed in muscle tissue. As the muscle fiber microenvironment is abnormal in congenital muscular dystrophies and cell-matrix adhesions are weakened, studies elucidating how strong, stable cell-matrix adhesions form in development could be informative in the effort to treat congenital muscular dystrophies.
Using this approach, we identified a previously undescribed cell-matrix adhesion pathway required for normal organization of an important substructure in the muscle tissue microenvironment. We show that activation of this cell-matrix adhesion pathway in dystrophic zebrafish not only significantly reduces muscle degeneration, but also improves swimming ability. The results presented in this dissertation identify proteins that function in this cell-matrix adhesion pathway and use dystrophic zebrafish to show the benefits and limitations of this pathway in treating symptoms of congenital muscular dystrophies. Our findings suggest that activation of this pathway has the potential to ameliorate loss of muscle structure and function in multiple muscular dystrophies.

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