The inhibitory core of the myostatin prodomain: Its interaction with both type I and II membrane receptors, and potential to treat muscle atrophy

Yutaka Ohsawa, Kentaro Takayama, Shin Ichiro Nishimatsu, Tadashi Okada, Masahiro Fujino, Yuta Fukai, Tatsufumi Murakami, Hiroki Hagiwara, Fumiko Itoh, Kunihiro Tsuchida, Yoshio Hayashi, Yoshihide Sunada

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Abstract

Myostatin, a muscle-specific transforming growth factor-β (TGF-β), negatively regulates skeletal muscle mass. The N-terminal prodomain of myostatin noncovalently binds to and suppresses the C-terminal mature domain (ligand) as an inactive circulating complex. However, which region of the myostatin prodomain is required to inhibit the biological activity of myostatin has remained unknown. We identified a 29-amino acid region that inhibited myostatin-induced transcriptional activity by 79% compared with the full-length prodomain. This inhibitory core resides near the N-terminus of the prodomain and includes an α-helix that is evolutionarily conserved among other TGF-β family members, but suppresses activation of myostatin and growth and differentiation factor 11 (GDF11) that share identical membrane receptors. Interestingly, the inhibitory core co-localized and co-immunoprecipitated with not only the ligand, but also its type I and type II membrane receptors. Deletion of the inhibitory core in the full-length prodomain removed all capacity for suppression of myostatin. A synthetic peptide corresponding to the inhibitory core (p29) ameliorates impaired myoblast differentiation induced by myostatin and GDF11, but not activin or TGF-β1. Moreover, intramuscular injection of p29 alleviated muscle atrophy and decreased the absolute force in caveolin 3-deficient limb-girdle muscular dystrophy 1C model mice. The injection suppressed activation of myostatin signaling and restored the decreased numbers of muscle precursor cells caused by caveolin 3 deficiency. Our findings indicate a novel concept for this newly identified inhibitory core of the prodomain of myostatin: that it not only suppresses the ligand, but also prevents two distinct membrane receptors from binding to the ligand. This study provides a strong rationale for the use of p29 in the amelioration of skeletal muscle atrophy in various clinical settings.

Original languageEnglish
Article numbere0133713
JournalPloS one
Volume10
Issue number7
DOIs
Publication statusPublished - 30-07-2015

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Ohsawa, Y., Takayama, K., Nishimatsu, S. I., Okada, T., Fujino, M., Fukai, Y., Murakami, T., Hagiwara, H., Itoh, F., Tsuchida, K., Hayashi, Y., & Sunada, Y. (2015). The inhibitory core of the myostatin prodomain: Its interaction with both type I and II membrane receptors, and potential to treat muscle atrophy. PloS one, 10(7), [e0133713]. https://doi.org/10.1371/journal.pone.0133713