Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity

Abstract

Caveolin-3 is the muscle-specific isoform of the caveolin protein family, which is a major component of caveolae, small membrane invaginations found in most cell types. Caveolins play important roles in the formation of caveola membranes, acting as scaffolding proteins to organize and concentrate lipid-modified signaling molecules, and modulate a signaling pathway. For instance, caveolin-3 interacts with neuronal nitric oxide synthase (nNOS) and inhibits its catalytic activity. Recently, specific mutations in the caveolin-3 gene, including the Pro104Leu missense mutation, have been shown to cause an autosomal dominant limb-girdle muscular dystrophy (LGMD1C), which is characterized by the deficiency of caveolin-3 in the sarcolemma. However, the molecular mechanism by which these mutations cause the deficiency of caveolin-3 and muscle cell degeneration remains elusive. Here we generated transgenic mice expressing the Pro104Leu mutant caveolin-3. They showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, indicating a dominant negative effect of mutant caveolin-3. Interestingly, we also found a great increase of nNOS activity in their skeletal muscle, which, we propose, may play a role in muscle fiber degeneration in caveolin-3 deficiency.

An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy

“…At 16 weeks of age, H&E-stained sections of quadriceps femoris muscles from both CAV3 P104L and wildtype mice were examined. As we reported previously, 5,11 CAV3 P104L mouse muscle (Figure 4d, upper) showed marked reduction of myofiber size, compared with wild-type mouse muscle (Figure 4d, lower). Conversely, Ki26894 treatment appeared to alleviate the reduced myofiber size in the CAV3 P104L mice.…”

“…11 These mice demonstrated myopathy characterized by muscle atrophy and loss of caveolin-3, with increased intramuscular TGF-b signal. 5,6,11 Ki26894 was mixed with normal powdered food (CE-2; CLEA, Hamamatsu, Shizuoka, Japan) to a final concentration of 0.08%, and was orally administered to caveolin 3-deficient transgenic mice (CAV3 P104L ) or control wild-type mice aged between 6 and 16 weeks, as described. 18 All animal experiments were performed at the Laboratory Animal Center and were approved by the Animal Research Committee of Kawasaki Medical School.…”

“…9,10 We previously developed a transgenic mouse overexpressing Pro104Leu mutant caveolin 3 (CAV3 P104L ) as a model of LGMD1C; these mice demonstrated myopathy characterized by muscle atrophy. 11 We found that the caveolin 3-deficient muscles in the transgenic mice showed activation of intramuscular transforming growth factor beta (TGF-b)-mediated signals, including myostatin, which is specifically expressed in skeletal muscle and negatively regulates muscle mass and growth. [5][6][7][8] However, the cellular pathobiology leading to muscle atrophy caused by the loss of caveolin 3 and activated intramuscular TGF-b signals remains to be elucidated.…”

Muscular atrophy of caveolin-3–deficient mice is rescued by myostatin inhibition

“…We previously generated Tg mice overexpressing the Pro104Leu mutant caveolin-3 (CAV-3 P104L ) as a model for LGMD1C (5). The skeletal muscle pathology of the Tg mice includes myopathy characterized by severe skeletal muscle atrophy and a deficiency in caveolin-3.…”

“…We previously generated CAV-3 P104L and MSTN Pro mice (5,12). Heterozygous mating of these mice gave rise to F1 offspring with 4 distinct genotypes: wild-type, mutant caveolin-3-Tg (CAV-3 P104L ), mutant myostatinTg (MSTN Pro ), and double Tg (CAV-3 P104L /MSTN Pro ).…”