The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy
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 p...
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| creator | Ohsawa, Yutaka Takayama, Kentaro Nishimatsu, Shin-ichiro Okada, Tadashi Fujino, Masahiro Fukai, Yuta Murakami, Tatsufumi Hagiwara, Hiroki Itoh, Fumiko Tsuchida, Kunihiro Hayashi, Yoshio Sunada, Yoshihide |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0133713 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0133713</identifier><identifier>PMID: 26226340</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Activin ; Activins - metabolism ; Amino acids ; Animals ; Atrophy ; Binding sites ; Biological activity ; Bone morphogenetic proteins ; Caveolin ; Caveolin 3 - metabolism ; Cell Differentiation - physiology ; Cell Line ; Cell Membrane Structures - metabolism ; Cercopithecus aethiops ; Clonal deletion ; Comparative analysis ; COS Cells ; Differentiation ; Dystrophy ; Growth Differentiation Factors - metabolism ; Growth factors ; HEK293 Cells ; Humans ; Injection ; Kinases ; Life sciences ; Ligands ; Male ; Medical research ; Medical schools ; Membranes ; Mice ; Muscle, Skeletal - metabolism ; Muscles ; Muscular Atrophy - metabolism ; Muscular Dystrophies, Limb-Girdle - metabolism ; Muscular dystrophy ; Musculoskeletal system ; Myoblasts - metabolism ; Myostatin ; Myostatin - metabolism ; N-Terminus ; Neurology ; Peptides ; Pharmaceutical sciences ; Pharmacy ; Protein Structure, Tertiary - physiology ; Proteins ; Receptors ; Receptors, Cell Surface - metabolism ; Rodents ; Signaling ; Skeletal muscle ; Transcription ; Transforming Growth Factor beta1 - metabolism ; Transforming growth factor-a ; Transforming growth factor-b ; Transforming growth factor-b1 ; Transforming growth factors</subject><ispartof>PloS one, 2015-07, Vol.10 (7), p.e0133713-e0133713</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Ohsawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Ohsawa et al 2015 Ohsawa et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-bbae0fc223d279a6c93a224cb6ec02acbf871ae759436c6831b3cc67ad72b6223</citedby><cites>FETCH-LOGICAL-c692t-bbae0fc223d279a6c93a224cb6ec02acbf871ae759436c6831b3cc67ad72b6223</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520684/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520684/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26226340$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Mouly, Vincent</contributor><creatorcontrib>Ohsawa, Yutaka</creatorcontrib><creatorcontrib>Takayama, Kentaro</creatorcontrib><creatorcontrib>Nishimatsu, Shin-ichiro</creatorcontrib><creatorcontrib>Okada, Tadashi</creatorcontrib><creatorcontrib>Fujino, Masahiro</creatorcontrib><creatorcontrib>Fukai, Yuta</creatorcontrib><creatorcontrib>Murakami, Tatsufumi</creatorcontrib><creatorcontrib>Hagiwara, Hiroki</creatorcontrib><creatorcontrib>Itoh, Fumiko</creatorcontrib><creatorcontrib>Tsuchida, Kunihiro</creatorcontrib><creatorcontrib>Hayashi, Yoshio</creatorcontrib><creatorcontrib>Sunada, Yoshihide</creatorcontrib><title>The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Activation</subject><subject>Activin</subject><subject>Activins - metabolism</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Atrophy</subject><subject>Binding sites</subject><subject>Biological activity</subject><subject>Bone morphogenetic proteins</subject><subject>Caveolin</subject><subject>Caveolin 3 - metabolism</subject><subject>Cell Differentiation - physiology</subject><subject>Cell Line</subject><subject>Cell Membrane Structures - metabolism</subject><subject>Cercopithecus aethiops</subject><subject>Clonal deletion</subject><subject>Comparative analysis</subject><subject>COS Cells</subject><subject>Differentiation</subject><subject>Dystrophy</subject><subject>Growth Differentiation Factors - metabolism</subject><subject>Growth factors</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Injection</subject><subject>Kinases</subject><subject>Life sciences</subject><subject>Ligands</subject><subject>Male</subject><subject>Medical research</subject><subject>Medical schools</subject><subject>Membranes</subject><subject>Mice</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscles</subject><subject>Muscular Atrophy - metabolism</subject><subject>Muscular Dystrophies, Limb-Girdle - metabolism</subject><subject>Muscular dystrophy</subject><subject>Musculoskeletal system</subject><subject>Myoblasts - metabolism</subject><subject>Myostatin</subject><subject>Myostatin - metabolism</subject><subject>N-Terminus</subject><subject>Neurology</subject><subject>Peptides</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacy</subject><subject>Protein Structure, Tertiary - physiology</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Receptors, Cell Surface - 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ohsawa, Yutaka</au><au>Takayama, Kentaro</au><au>Nishimatsu, Shin-ichiro</au><au>Okada, Tadashi</au><au>Fujino, Masahiro</au><au>Fukai, Yuta</au><au>Murakami, Tatsufumi</au><au>Hagiwara, Hiroki</au><au>Itoh, Fumiko</au><au>Tsuchida, Kunihiro</au><au>Hayashi, Yoshio</au><au>Sunada, Yoshihide</au><au>Mouly, Vincent</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-07-30</date><risdate>2015</risdate><volume>10</volume><issue>7</issue><spage>e0133713</spage><epage>e0133713</epage><pages>e0133713-e0133713</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26226340</pmid><doi>10.1371/journal.pone.0133713</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-07, Vol.10 (7), p.e0133713-e0133713 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1700336392 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Activin Activins - metabolism Amino acids Animals Atrophy Binding sites Biological activity Bone morphogenetic proteins Caveolin Caveolin 3 - metabolism Cell Differentiation - physiology Cell Line Cell Membrane Structures - metabolism Cercopithecus aethiops Clonal deletion Comparative analysis COS Cells Differentiation Dystrophy Growth Differentiation Factors - metabolism Growth factors HEK293 Cells Humans Injection Kinases Life sciences Ligands Male Medical research Medical schools Membranes Mice Muscle, Skeletal - metabolism Muscles Muscular Atrophy - metabolism Muscular Dystrophies, Limb-Girdle - metabolism Muscular dystrophy Musculoskeletal system Myoblasts - metabolism Myostatin Myostatin - metabolism N-Terminus Neurology Peptides Pharmaceutical sciences Pharmacy Protein Structure, Tertiary - physiology Proteins Receptors Receptors, Cell Surface - metabolism Rodents Signaling Skeletal muscle Transcription Transforming Growth Factor beta1 - metabolism Transforming growth factor-a Transforming growth factor-b Transforming growth factor-b1 Transforming growth factors |
| title | The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy |
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