Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype

Abstract

It recently was reported that Duchenne muscular dystrophy (DMD) patients and mdx mice have elevated levels of caveolin-3 expression in their skeletal muscle. However, it remains unknown whether increased caveolin-3 levels in DMD patients contribute to the pathogenesis of DMD. Here, using a genetic approach, we test this hypothesis directly by overexpressing wild-type caveolin-3 as a transgene in mice. Analysis of skeletal muscle tissue from caveolin-3-overexpressing transgenic mice reveals: (i) a dramatic increase in the number of sarcolemmal muscle cell caveolae; (ii) a preponderance of hypertrophic, necrotic, and immature͞regener-ating skeletal muscle fibers with characteristic central nuclei; and (iii) down-regulation of dystrophin and ␤-dystroglycan protein expression. In addition, these mice show elevated serum creatine kinase levels, consistent with the myo-necrosis observed morphologically. The Duchenne-like phenotype of caveolin-3 transgenic mice will provide an important mouse model for understanding the pathogenesis of DMD in humans.

Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

“…12 Conversely, transgenic over-expression of Cav-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype, and causes the down-regulation of dystrophin and of dystrophin-associated proteins. 39 Taken together, these results suggest that a particular ratio between Cav-3 and dystrophin may be crucial for the proper functioning of skeletal muscle. Recent studies have attempted to gain insight in the molecular basis of these observations, and have demonstrated that Cav-3 directly interacts with ␤-dystroglycan, at the same or an overlapping site as dystrophin.…”

Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

“…21 In addition, Cav-3 was shown to bind b-dystroglycan at a similar or overlapping site as dystrophin, thus indicating that Cav-3 and dystrophin may compete for the binding site to b-dystroglycan, and that Cav-3 expression levels may regulate the recruitment of dystrophin to the plasma membrane. 30 Thus, we tested whether MLN273 treatment would decrease abnormally elevated Cav-3 levels in mdx skeletal muscles, which maybe important for improvement of pathological signs.…”

“…For example, Cav-3 is increased in skeletal muscle fibers from mdx mice and DMD patients, 9,10 whereas transgenic over-expression of Cav-3 in skeletal muscles induces a Duchenne-like phenotype. 21 As such, we assessed whether treatment with MLN273 would normalize Cav-3 expression levels. Figure 4 shows that treatment with all three concentrations (20 mM, 100 mM and 160 mM) of MLN273 induces Immunohistochemistry.…”

Oxidative Stress Induces Premature Senescence by Stimulating Caveolin-1 Gene Transcription through p38 Mitogen-Activated Protein Kinase/Sp1–Mediated Activation of Two GC-Rich Promoter Elements

“…Caveolin-1 and caveolin-2 are coexpressed in many cell types, including adipocytes, endothelial cells, epithelial cells, and fibroblasts (9). In contrast, caveolin-3 expression is essentially restricted to skeletal and smooth muscle cells, as well as cardiac myocytes (10)(11)(12)(13)(14)(15)(16)(17)(18). The direct interaction with caveolin-1 results in the inhibition of a number of signaling molecules, such as G-protein a subunit, Ras, nitric oxide synthase, protein kinase C, and protein kinase A (2,7,10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”