| RRC ID |
45476
|
| Author |
Ohsawa Y, Takayama K, Nishimatsu S, Okada T, Fujino M, Fukai Y, Murakami T, Hagiwara H, Itoh F, Tsuchida K, Hayashi Y, Sunada Y.
|
| Title |
The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy.
|
| Journal |
PLoS One
|
| 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.
|
| Volume |
10(7)
|
| Pages |
e0133713
|
| Published |
2015-1-1
|
| DOI |
10.1371/journal.pone.0133713
|
| PII |
PONE-D-14-50891
|
| PMID |
26226340
|
| PMC |
PMC4520684
|
| MeSH |
Activins / metabolism
Animals
COS Cells
Caveolin 3 / metabolism
Cell Differentiation / physiology
Cell Line
Cell Membrane Structures / metabolism
Chlorocebus aethiops
Growth Differentiation Factors / metabolism
HEK293 Cells
Humans
Ligands
Male
Mice
Muscle, Skeletal / metabolism
Muscular Atrophy / metabolism*
Muscular Dystrophies, Limb-Girdle / metabolism
Myoblasts / metabolism
Myostatin / metabolism*
Protein Structure, Tertiary / physiology
Receptors, Cell Surface / metabolism*
Transforming Growth Factor beta1 / metabolism
|
| IF |
2.74
|
| Times Cited |
17
|
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| Human and Animal Cells |
COS-7(RCB0539)
293(RCB1637)
C2C12(RCB0987) |
