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

Yutaka Ohsawa, Hiroki Hagiwara, Masashi Nakatani, Akihiro Yasue, Keiji Moriyama, Tatsufumi Murakami, Kunihiro Tsuchida, Sumihare Noji, Yoshihide Sunada

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2924-2934
Number of pages11
JournalJournal of Clinical Investigation
Volume116
Issue number11
DOIs
Publication statusPublished - 01-11-2006

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Caveolin 3
Myostatin
Muscular Atrophy
Limb-Girdle Muscular Dystrophies
Muscles
Transgenic Mice
Caveolins
Genes
Signal Transduction
Protein Isoforms
Skeletal Muscle

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Ohsawa, Y., Hagiwara, H., Nakatani, M., Yasue, A., Moriyama, K., Murakami, T., ... Sunada, Y. (2006). Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition. Journal of Clinical Investigation, 116(11), 2924-2934. https://doi.org/10.1172/JCI28520
Ohsawa, Yutaka ; Hagiwara, Hiroki ; Nakatani, Masashi ; Yasue, Akihiro ; Moriyama, Keiji ; Murakami, Tatsufumi ; Tsuchida, Kunihiro ; Noji, Sumihare ; Sunada, Yoshihide. / Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 11. pp. 2924-2934.
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abstract = "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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Ohsawa, Y, Hagiwara, H, Nakatani, M, Yasue, A, Moriyama, K, Murakami, T, Tsuchida, K, Noji, S & Sunada, Y 2006, 'Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition', Journal of Clinical Investigation, vol. 116, no. 11, pp. 2924-2934. https://doi.org/10.1172/JCI28520

Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition. / Ohsawa, Yutaka; Hagiwara, Hiroki; Nakatani, Masashi; Yasue, Akihiro; Moriyama, Keiji; Murakami, Tatsufumi; Tsuchida, Kunihiro; Noji, Sumihare; Sunada, Yoshihide.

In: Journal of Clinical Investigation, Vol. 116, No. 11, 01.11.2006, p. 2924-2934.

Research output: Contribution to journalArticle

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T1 - Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition

AU - Ohsawa, Yutaka

AU - Hagiwara, Hiroki

AU - Nakatani, Masashi

AU - Yasue, Akihiro

AU - Moriyama, Keiji

AU - Murakami, Tatsufumi

AU - Tsuchida, Kunihiro

AU - Noji, Sumihare

AU - Sunada, Yoshihide

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N2 - 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.

AB - 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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