Fiber regeneration is not persistent in dystrophic (mdx) mouse skeletal muscle

DiMario, Joseph X.; Uzman, Akif; Strohman, Richard C.

doi:10.1016/0012-1606(91)90340-9

Cited by 185 publications

(142 citation statements)

References 35 publications

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“…Previous studies in mdx mice, a mouse model of muscular dystrophy caused by dystrophin deficiency, demonstrated that the myofiber number in atrophic muscles was not decreased compared with skeletal muscles from control mice (32,33). Thus, both muscle hypoplasia and hypotrophy are characteristic of caveolin-3 deficiency.…”

Section: Discussionmentioning

confidence: 90%

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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Section: Discussionmentioning

confidence: 90%

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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“…The mdx mouse strain displays critical hallmarks of the human form of DMD, including high susceptibility to contraction-induced damage and increased muscle degeneration and regeneration (7)(8)(9). Extensor digitorum longus (EDL) muscles from mdx mice electroporated with 10 μg of Wnt7a expression plasmid exhibited a 25% increase in muscle wet weight (n = 7; P < 0.01), compared with a 45% increase in WT mice (n = 7; P < 0.004) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Wnt7a treatment ameliorates muscular dystrophy

Maltzahn

Renaud

Parise

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

101

104

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Duchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder of childhood marked by progressive debilitating muscle weakness and wasting, and ultimately death in the second or third decade of life. Wnt7a signaling through its receptor Fzd7 accelerates and augments regeneration by stimulating satellite stem cell expansion through the planar cell polarity pathway, as well as myofiber hypertrophy through the AKT/mammalian target of rapamycin (mTOR) anabolic pathway. We investigated the therapeutic potential of the secreted factor Wnt7a for focal treatment of dystrophic DMD muscles using the mdx mouse model, and found that Wnt7a treatment efficiently induced satellite cell expansion and myofiber hypertrophy in treated mucles in mdx mice. Importantly, Wnt7a treatment resulted in a significant increase in muscle strength, as determined by generation of specific force. Furthermore, Wnt7a reduced the level of contractile damage, likely by inducing a shift in fiber type toward slow-twitch. Finally, we found that Wnt7a similarly induced myotube hypertrophy and a shift in fiber type toward slow-twitch in human primary myotubes. Taken together, our findings suggest that Wnt7a is a promising candidate for development as an ameliorative treatment for DMD.noncanonical Wnt signaling | skeletal muscle D uchenne muscular dystrophy (DMD) is a degenerative disorder characterized by muscle weakness and fragility. It is caused by mutations in the X-linked dystrophin gene, affecting 1 in 3,500 newborn males. Dystrophin deficiency results in the disruption of the dystrophin-glycoprotein complex, preventing binding of the actin cytoskeleton to the extracellular matrix. This leads to tearing of the muscle fibers during contraction, resulting in muscle damage, especially in fast fibers (1, 2). The muscle itself cannot compensate for this immense structural damage, ultimately leading to loss of muscle fibers, increased fibrosis, and reduced force generated by the muscle (3).Satellite stem cells represent a small subpopulation of satellite cells capable of self-renewal and long-term reconstitution of the satellite cell niche after transplantation (4). Previously, we found that the noncanonical Wnt receptor Fzd7 is specifically expressed in satellite stem cells. Recombinant Wnt7a protein dramatically stimulates the symmetric expansion of satellite stem cells, a process requiring both Fzd7 and Vangl2, components of the planar cell polarity signaling pathway. Overexpression of Wnt7a during muscle regeneration results in impressive enhancement of the regeneration process, generating fibers of larger caliber (5). In recent studies, we observed that binding of Wnt7a to Fzd7 directly activates the AKT/mammalian target of rapamycin (mTOR) pathway, thereby inducing myofiber hypertrophy. Notably, association of Fzd7 with PI3kinase is required for Wnt7a to activate the anabolic AKT/mTOR pathway. Wnt7a/Fzd7-mediated induction of this pathway is entirely independent of IGF (Insulin-like growth factor-1) receptor activation (6).Our experi...

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“…Similar to DMD patients, the mdx mouse lacks dystrophin. It was reported that, in somite-derived muscles of the extremities, muscle necrosis began at 2 weeks after birth, immediately followed by regeneration, and the majority of necrotic muscles became regenerated at 4 weeks after birth (Dangain et al 1984;DiMario et al 1991;Attal et al 2000). A similar phenomenon was noted in the branchial arch-derived mdx mouse masseter muscle (Lee et al 2006), and cell degeneration in this muscular dystrophy was ascribed to the lack of dystrophin, resulting in damage to cell membrane stability, leading to excessive influx of calcium ions into muscle cells, a mechanism similar to that of necrosis.…”

Section: Introductionmentioning

confidence: 99%

Activation of caspase 3, 9, 12, and Bax in masseter muscle of mdx mice during necrosis

Honda

Abe

Hiroki

et al. 2007

J Muscle Res Cell Motil

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The mdx mouse, a model of muscular dystrophy, lacks dystrophin, a cell membrane protein. It is known that the lack of dystrophin causes muscle fiber necrosis from 2 weeks after birth, and the majority of necrotic muscle fibers are replaced by regenerated muscle fibers by 4 weeks after birth. A recent study indicated the possibility that mitochondria-mediated intracellular stress, a phenomenon similar to apoptosis, may be produced during muscle fiber necrosis, but did not analyze endoplasmic reticulum-mediated intracellular stress.Therefore, we examined the expression of the caspase-12 gene involved in the endoplasmic reticulum stress pathway and the Bax, caspase-9, and caspase-3 genes involved in the mitochondrial stress pathway in the mdx masseter muscle. We found over-expression of caspase-12 in cells at 2-3 weeks after birth when muscle fiber necrosis was not prominent. This suggests that s tress occurs in the endoplasmic reticulum to maintain cell morphology in the absence of dystrophin. In addition, Bax was abundantly expressed in the mdx masseter muscle at 3 weeks after birth, and the expression of caspase-9 and -3 was prominent at 3-4 weeks after birth when necrosis and regeneration were marked. These results indicate that endoplasmic reticulum and mitochondrial stresses are produced during necrosis of 3 the mdx masseter muscle, and suggest that these events are a phenomenon similar to apoptosis.

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Fiber regeneration is not persistent in dystrophic (mdx) mouse skeletal muscle

Cited by 185 publications

References 35 publications

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

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

Wnt7a treatment ameliorates muscular dystrophy

Activation of caspase 3, 9, 12, and Bax in masseter muscle of mdx mice during necrosis

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