A caveolin-3 mutant that causes limb girdle muscular dystrophy type 1C disrupts Src localization and activity and induces apoptosis in skeletal myotubes

Smythe, Gayle M.; Eby, Joshua; Disatnik, Marie‐Hélène; Rando, Thomas A.

doi:10.1242/jcs.00806

Cited by 52 publications

(60 citation statements)

References 48 publications

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“…Caveolin-3 can elicit survival signalling in muscle, as can Pax7. Our data suggest a direct role for caveolin-3 in the rapid loss of Pax7-positive myoblasts at E15.5 in cav-3 -/-mutants, and suggest that the attrition of Pax7-positive myoblasts could be partially compensated for in mdx muscles by their increased caveolin-3 levels (Relaix et al, 2006;Smythe et al, 2003). This conclusion is supported by the finding that, in mdxcav-3 +/-mutants, Pax7 is depleted substantially more than in either single mutant, such that, by E17.5, Pax7 cells are entirely absent in mdxcav-3 +/-lower proximal limb muscles and are very much reduced in other muscles.…”

Section: Loss Of Pax7 Myoblastsmentioning

confidence: 66%

“…Patients with LGMD-1c exhibit similar, but restricted, myopathic changes that particularly affect the muscles of the limb, diaphragm and heart (Galbiati et al, 2001;Hagiwara et al, 2000;Smythe et al, 2003). In most respects, the mdx and cav-3 -/-postnatal phenotypes are sufficiently similar to the clinical pathologies of DMD and LGMD to be used widely as disease models (Chamberlain et al, 2007;Chan et al, 2007;Galbiati et al, 2001;Hagiwara et al, 2000;Roig et al, 2004;Vaghy et al, 1998).…”

Section: Loss Of Pax7 Myoblastsmentioning

confidence: 99%

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Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation

Merrick

Stadler

Larner

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARYExamination of embryonic myogenesis of two distinct, but functionally related, skeletal muscle dystrophy mutants (mdx and cav-3 -/-) establishes for the first time that key elements of the pathology of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy type 1C (LGMD1c) originate in the disruption of the embryonic cardiac and skeletal muscle patterning processes. Disruption of myogenesis occurs earlier in mdx mutants, which lack a functional form of dystrophin, than in cav-3 -/-mutants, which lack the Cav3 gene that encodes the protein caveolin-3; this finding is consistent with the milder phenotype of LGMD-1c, a condition caused by mutations in Cav3, and the earlier [embryonic day (E)9.5] expression of dystrophin. Myogenesis is severely disrupted in mdx embryos, which display developmental delays; myotube morphology and displacement defects; and aberrant stem cell behaviour. In addition, the caveolin-3 protein is elevated in mdx embryos. Both cav-3 -/-and mdx mutants (from E15.5 and E11.5, respectively) exhibit hyperproliferation and apoptosis of Myf5-positive embryonic myoblasts; attrition of Pax7-positive myoblasts in situ; and depletion of total Pax7 protein in late gestation. Furthermore, both cav-3 -/-and mdx mutants have cardiac defects. In cav-3 -/-mutants, there is a more restricted phenotype comprising hypaxial muscle defects, an excess of malformed hypertrophic myotubes, a twofold increase in myonuclei, and reduced fast myosin heavy chain (FMyHC) content. Several mdx mutant embryo pathologies, including myotube hypotrophy, reduced myotube numbers and increased FMyHC, have reciprocity with cav-3 -/-mutants. In double mutant (mdxcav-3) embryos that are deficient in dystrophin (mdx) and heterozygous for caveolin-3 (cav-3), whereby caveolin-3 is reduced to 50% of wild-type (WT) levels, these phenotypes are severely exacerbated: intercostal muscle fibre density is reduced by 71%, and Pax7-positive cells are depleted entirely from the lower limbs and severely attenuated elsewhere; these data suggest a compensatory rather than a contributory role for the elevated caveolin-3 levels that are found in mdx embryos. These data establish a key role for dystrophin in early muscle formation and demonstrate that caveolin-3 and dystrophin are essential for correct fibre-type specification and emergent stem cell function. These data plug a significant gap in the natural history of muscular dystrophy and will be invaluable in establishing an earlier diagnosis for DMD/LGMD and in designing earlier treatment protocols, leading to better clinical outcome for these patients.

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Section: Loss Of Pax7 Myoblastsmentioning

confidence: 66%

Section: Loss Of Pax7 Myoblastsmentioning

confidence: 99%

Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation

Merrick

Stadler

Larner

et al. 2009

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…We also found a significant increase in neuronal nitric oxide synthase activity in their skeletal muscle. Other groups have demonstrated mislocalization of Src and dysferlin to the Golgi apparatus (6,7). Despite these findings, the precise molecular mechanism leading to muscular atrophy in caveolin-3-deficient skeletal muscle remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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

Ohsawa¹,

Hagiwara²,

Nakatani³

et al. 2006

J. Clin. Invest.

101

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Caveolin-3, the muscle-specific isoform of caveolins, plays important roles in signal transduction. Dominant-negative mutations of the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C) with loss of caveolin-3. However, identification of the precise molecular mechanism leading to muscular atrophy in caveolin-3-deficient muscle has remained elusive. Myostatin, a member of the muscle-specific TGF-β superfamily, negatively regulates skeletal muscle volume. Here we report that caveolin-3 inhibited myostatin signaling by suppressing activation of its type I receptor; this was followed by hypophosphorylation of an intracellular effector, Mad homolog 2 (Smad2), and decreased downstream transcriptional activity. Loss of caveolin-3 in P104L mutant caveolin-3 transgenic mice caused muscular atrophy with increase in phosphorylated Smad2 (p-Smad2) as well as p21 (also known as Cdkn1a), a myostatin target gene. Introduction of the myostatin prodomain, an inhibitor of myostatin, by genetic crossing or intraperitoneal administration of the soluble type II myostatin receptor, another inhibitor, ameliorated muscular atrophy of the mutant caveolin-3 transgenic mice with suppression of p-Smad2 and p21 levels. These findings suggest that caveolin-3 normally suppresses the myostatin-mediated signal, thereby preventing muscular atrophy, and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in a mouse model of LGMD1C. Myostatin inhibition may be a promising therapy for LGMD1C patients.

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“…Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle Until now, the role of caveolin-1 in insulin signaling in muscle tissue has received little attention, probably caveolin-3 is expressed in a muscle specific manner and mutation of caveolin-3 cause limb girdle muscular dystrophy leading to apoptosis of skeletal muscle (Capanni et al, 2003;Smythe et al, 2003). However, it was not clear whether insulin resistance was induced by caveolin-3 deficiency or by muscle abnormality.…”

Section: Introductionmentioning

confidence: 99%

Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle

Kim²,

Ryu³

et al. 2007

Exp Mol Med

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It is well known that exercise can have beneficial effects on insulin resistance by activation of glucose transporter. Following up our previous report that caveolin-1 plays an important role in glucose uptake in L6 skeletal muscle cells, we examined whether exercise alters the expression of caveolin-1, and whether exercise-caused changes are muscle fiber and exercise type specific. Fifity week-old Sprague Dawley (SD) rats were trained to climb a ladder and treadmill for 8 weeks and their soleus muscles (SOL) and extensor digitorum longus muscles (EDL) were removed after the last bout of exercise and compared with those from non-exercised animals. We found that the expression of insulin related proteins and caveolins did not change in SOL muscles after exercise. However, in EDL muscles, the expression of insulin receptor β (IRβ) and glucose transporter-4 (GLUT-4) as well as phosphorylation of AKT and AMPK increased with resistance exercise but not with aerobic exercise. Also, caveolin-1 and caveolin-3 increased along with insulin related proteins only in EDL muscles by resistance exercise. These results suggest that upregulation of caveolin-1 in the skeletal muscle is fiber specific and exercise type specific, implicating the requirement of the specific mode of exercise to improve insulin sensitivity.

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A caveolin-3 mutant that causes limb girdle muscular dystrophy type 1C disrupts Src localization and activity and induces apoptosis in skeletal myotubes

Cited by 52 publications

References 48 publications

Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation

Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation

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

Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle

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