Gene expression analysis of skeletal muscle from mutant caveolin-3 (P104L) transgenic mice: apoptotic signaling trends *
Caveolins are membrane proteins which are the principal components of caveolae, flask-shaped invaginations of the plasma membrane. Caveolin-3 is the muscle specific isoform of the caveolin protein family. Specific mutations in the caveolin-3 gene, including the Pro 104 Leu missense mutation, cause a deficiency in caveolin-3 in the sarcolemma and contribute to an autosomal dominant limb-girdle muscular dystrophy (LGMD1C). The molecular mechanism by which these mutations cause the deficiency in caveolin-3 in the sarcolemma leading to muscle cell degeneration remains unknown. Sunada et al generated transgenic (Tg) mice expressing the Pro 104 Leu missense mutation. Those Tg mice showed a severe myopathic phenotype concomitant with an excessive expression of the mutant caveolin-3. However, they showed a deficiency in caveolin-3 in the sarcolemma, indicating a dominant negative effect of the mutant caveolin-3. The Tg mice showed a great increase in nNOS activity in skeletal muscle. For the screening of genes involved in the pathogenesis of caveolin-3 deficiency, I did gene expression pro filing using a DNA membrane array and gene chip technology, and found many up-regulated or down-regulated genes in Tg mice skeletal muscle. Northern blot analysis revealed upregulation of several apoptosis-related genes. In addition, several anti-apoptotic genes were also up-regulated, probably due to a defense mechanism to prevent muscle cell death. These results suggest that a caveolin-3 deficiency leads to alteration in apoptotic signaling pathways and results in muscle degeneration. (Accepted on October 25, 2003)
