Congenital muscular dystrophy: early pathology and combinatorial treatment strategies
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Abstract
MDC1A, the second most prevalent form of congenital muscular dystrophy, is an aggressive disease characterized by severe muscle weakness, hypotonia, contractures, spinal deformities, and premature death due to respiratory complications or failure to thrive. MDC1A results from mutation of the LAMA2 gene, which encodes for the laminin-a2 chain of laminin 211. Laminin 211 is an extracellular matrix protein predominantly expressed in the basal lamina of skeletal muscle and Schwann cells. As laminin 211 has multiple binding partners in the extracellular matrix and at the cell membrane, defects in laminin-a2 result in major disruption of the structural stability and signal transduction at the plasma membrane. This leads to apoptosis, chronic inflammation, failed regeneration, fibrosis and muscle wasting, all of which contributes to muscle loss. While the majority of studies have only analyzed adult muscles with laminin-a2 deficiency, very little is known about the early pathology associated with this disease. Lama2Dy-w mice (a mouse model for MDC1A) were analyzed at postnatal weeks 1, 2, 3, and 4. Lama2Dy-w mice showed limited postnatal body and hind limb muscle growth. Histological analyses clearly showed that pathogenesis begins as early as week 1 in Lama2Dy-w muscles. At 1 week, laminin-a2-deficient muscles have large regions of interstitial space filled with many mononucleated cells. In addition, we show that inflammation likely plays an earlier role than fibrosis in the pathology of Lama2Dy-w mice. As there is no cure or effective therapy currently available to MDC1A patients and no single treatment has been shown to completely improve the outcome of laminin-a2 deficiency, we tested a combinatorial therapy strategy that targeted two pathophysiological processes affected in this disease: apoptosis and failed regeneration. Apoptosis was inhibited by blocking the expression of the pro-apoptotic protein Bax, while regeneration was enhanced by overexpressing insulin-like growth factor in Lama2Dy-w mice. The combined therapy group showed the greatest increase in body and muscle weights, activity, and muscle phenotype, as well as reduced fibrosis. Thus, the combination of Bax inhibition alongside IGF-1 overexpression had additive effects in improving the Lama2Dy-w
phenotype, suggesting that a combinatorial treatment approach could also have benefits in human patients.
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Thesis (M.S.)--Boston University
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