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Regulation of slow and fast muscle myofibrillogenesis by Wnt/beta-catenin and myostatin signaling.

Tee JM, van Rooijen C, Boonen R, Zivkovic D - PLoS ONE (2009)

Bottom Line: Deviation from proper muscle development or homeostasis results in various myopathic conditions.Employing genetic as well as chemical intervention, we provide evidence that a tight regulation of Wnt/beta-catenin signaling is essential for muscle fiber growth and maintenance.Epistatic analyses suggest a possible genetic interaction between Wnt/beta-catenin and Myostatin in regulation of slow and fast twitch muscle myofibrillogenesis.

View Article: PubMed Central - PubMed

Affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Center, Utrecht, The Netherlands.

ABSTRACT
Deviation from proper muscle development or homeostasis results in various myopathic conditions. Employing genetic as well as chemical intervention, we provide evidence that a tight regulation of Wnt/beta-catenin signaling is essential for muscle fiber growth and maintenance. In zebrafish embryos, gain-of-Wnt/beta-catenin function results in unscheduled muscle progenitor proliferation, leading to slow and fast muscle hypertrophy accompanied by fast muscle degeneration. The effects of Wnt/beta-catenin signaling on fast muscle hypertrophy were rescued by misexpression of Myostatin or p21(CIP/WAF), establishing an in vivo regulation of myofibrillogenesis by Wnt/beta-catenin signaling and Myostatin. Epistatic analyses suggest a possible genetic interaction between Wnt/beta-catenin and Myostatin in regulation of slow and fast twitch muscle myofibrillogenesis.

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Misexpression of mstn rescues axin1/apc1 embryos.(A) Injection of 5 pg p21CIP/WAF or mstn mRNA into 1 cell stage embryos, and phenotype assessment at 54 hpf. Slightly hypotrophic muscle fibers are observed in p21 as well as mstn-injected wild-type embryos confirming efficiency of misexpression. Muscle hypertrophy in mstn-injected axin1/apc1 embryos is partially restored to normal. (B) Quantification of the somite number of uninjected and p21CIP/WAF or mstn mRNA (5 pg) injected embryos. (C) Misexpression of mstn partially restores the truncated somite phenotype, as well as cell survival in axin1/apc1. Scale bar, 0.5 mm.
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pone-0005880-g005: Misexpression of mstn rescues axin1/apc1 embryos.(A) Injection of 5 pg p21CIP/WAF or mstn mRNA into 1 cell stage embryos, and phenotype assessment at 54 hpf. Slightly hypotrophic muscle fibers are observed in p21 as well as mstn-injected wild-type embryos confirming efficiency of misexpression. Muscle hypertrophy in mstn-injected axin1/apc1 embryos is partially restored to normal. (B) Quantification of the somite number of uninjected and p21CIP/WAF or mstn mRNA (5 pg) injected embryos. (C) Misexpression of mstn partially restores the truncated somite phenotype, as well as cell survival in axin1/apc1. Scale bar, 0.5 mm.

Mentions: Reportedly, Wnt/β-catenin through its direct target c-myc, can downregulate p21CIP/WAF (also known as cyclin-dependent kinase inhibitor 1A) [31]. We hypothesized that sustained myotomal proliferation in axin1/apc1 mutants works through Wnt/β-catenin-mediated inhibition of p21CIP/WAF. We tested the hypothesis by examining the capacity of p21CIP/WAF mRNA injected into axin1/apc1 mutant to rescue muscle fiber phenotype. Employing misexpression with p21CIP/WAF mRNA concentration that only subtly affected the wildtypes, muscle fiber hypertrophy was rescued in injected axin1/apc1 embryos (Fig. 5A), suggesting that muscle fiber degeneration is due to hyperproliferation caused by failure of timely p21CIP/WAF-dependent cell cycle exit. However, we cannot exclude the possibility that forced cell cycle exit mediated by p21CIP/WAF misexpression in itself, and independently of its postulated positioning downstream of the Wnt pathway, may have brought about the rescue.


Regulation of slow and fast muscle myofibrillogenesis by Wnt/beta-catenin and myostatin signaling.

Tee JM, van Rooijen C, Boonen R, Zivkovic D - PLoS ONE (2009)

Misexpression of mstn rescues axin1/apc1 embryos.(A) Injection of 5 pg p21CIP/WAF or mstn mRNA into 1 cell stage embryos, and phenotype assessment at 54 hpf. Slightly hypotrophic muscle fibers are observed in p21 as well as mstn-injected wild-type embryos confirming efficiency of misexpression. Muscle hypertrophy in mstn-injected axin1/apc1 embryos is partially restored to normal. (B) Quantification of the somite number of uninjected and p21CIP/WAF or mstn mRNA (5 pg) injected embryos. (C) Misexpression of mstn partially restores the truncated somite phenotype, as well as cell survival in axin1/apc1. Scale bar, 0.5 mm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690692&req=5

pone-0005880-g005: Misexpression of mstn rescues axin1/apc1 embryos.(A) Injection of 5 pg p21CIP/WAF or mstn mRNA into 1 cell stage embryos, and phenotype assessment at 54 hpf. Slightly hypotrophic muscle fibers are observed in p21 as well as mstn-injected wild-type embryos confirming efficiency of misexpression. Muscle hypertrophy in mstn-injected axin1/apc1 embryos is partially restored to normal. (B) Quantification of the somite number of uninjected and p21CIP/WAF or mstn mRNA (5 pg) injected embryos. (C) Misexpression of mstn partially restores the truncated somite phenotype, as well as cell survival in axin1/apc1. Scale bar, 0.5 mm.
Mentions: Reportedly, Wnt/β-catenin through its direct target c-myc, can downregulate p21CIP/WAF (also known as cyclin-dependent kinase inhibitor 1A) [31]. We hypothesized that sustained myotomal proliferation in axin1/apc1 mutants works through Wnt/β-catenin-mediated inhibition of p21CIP/WAF. We tested the hypothesis by examining the capacity of p21CIP/WAF mRNA injected into axin1/apc1 mutant to rescue muscle fiber phenotype. Employing misexpression with p21CIP/WAF mRNA concentration that only subtly affected the wildtypes, muscle fiber hypertrophy was rescued in injected axin1/apc1 embryos (Fig. 5A), suggesting that muscle fiber degeneration is due to hyperproliferation caused by failure of timely p21CIP/WAF-dependent cell cycle exit. However, we cannot exclude the possibility that forced cell cycle exit mediated by p21CIP/WAF misexpression in itself, and independently of its postulated positioning downstream of the Wnt pathway, may have brought about the rescue.

Bottom Line: Deviation from proper muscle development or homeostasis results in various myopathic conditions.Employing genetic as well as chemical intervention, we provide evidence that a tight regulation of Wnt/beta-catenin signaling is essential for muscle fiber growth and maintenance.Epistatic analyses suggest a possible genetic interaction between Wnt/beta-catenin and Myostatin in regulation of slow and fast twitch muscle myofibrillogenesis.

View Article: PubMed Central - PubMed

Affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Center, Utrecht, The Netherlands.

ABSTRACT
Deviation from proper muscle development or homeostasis results in various myopathic conditions. Employing genetic as well as chemical intervention, we provide evidence that a tight regulation of Wnt/beta-catenin signaling is essential for muscle fiber growth and maintenance. In zebrafish embryos, gain-of-Wnt/beta-catenin function results in unscheduled muscle progenitor proliferation, leading to slow and fast muscle hypertrophy accompanied by fast muscle degeneration. The effects of Wnt/beta-catenin signaling on fast muscle hypertrophy were rescued by misexpression of Myostatin or p21(CIP/WAF), establishing an in vivo regulation of myofibrillogenesis by Wnt/beta-catenin signaling and Myostatin. Epistatic analyses suggest a possible genetic interaction between Wnt/beta-catenin and Myostatin in regulation of slow and fast twitch muscle myofibrillogenesis.

Show MeSH
Related in: MedlinePlus