GHRP-2, a GHS-R agonist, directly acts on myocytes to attenuate the dexamethasone-induced expressions of muscle-specific ubiquitin ligases, Atrogin-1 and MuRF1.
Recent reports suggest that Atrogin-1 and MuRF1, E3 ubiquitin ligases, play a pivotal role in muscle atrophy. In the present study, effect of Growth Hormone Releasing Peptide-2 (GHRP-2), a GH secretagogue receptor (GHS-R) agonist, on the expressions of Atrogin-1 and MuRF1 in vivo rat muscles was examined. Dexamethasone administration increased Atrogin-1 mRNA level in rat soleus muscle. The increased mRNA level of Atrogin-1 was significantly attenuated by GHRP-2. In addition, GHRP-2 decreased MuRF1 mRNA level irrespective of the presence of dexamethasone. Although IGF-I is a well-known protective factor for muscle atrophy, GHRP-2 did not influence plasma IGF-I levels and IGF-I mRNA levels in muscles. To clarify a direct effect of GHRP-2, differentiated C2C12 myocytes were used. Ten micrometer dexamethasone increased both Atrogin-1 and MuRF1 mRNA levels in C2C12 cells. GHRP-2 attenuated dexamethasone-induced expression of them dose-dependently and decreased the basal level of MuRF1 mRNA. The suppressive effect on the expressions of Atrogin-1 and MuRF1 by GHRP-2 was blocked by [D-Lys(3)]-GHRP-6, a GHS-R1a blocker, suggesting the effect of GHRP-2 was mediated through GHS-R1a. Taken together, GHRP-2 directly attenuates Atrogin-1 and MuRF1 mRNA levels through ghrelin receptors in myocytes.
Yamamoto
Daisuke
D
Department of Basic Allied Medicine, Kobe University School of Medicine, Kobe, Japan.
Ikeshita
Nobuko
N
Matsubara
Takako
T
Tasaki
Hiromitsu
H
Herningtyas
Elizabeth Henny
EH
Toda
Keizo
K
Iida
Keiji
K
Takahashi
Yutaka
Y
Kaji
Hidesuke
H
Chihara
Kazuo
K
Okimura
Yasuhiko
Y
D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D008297:Male; D051379:Mice; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics*; D009842:Oligopeptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D005938:Glucocorticoids; D009124:Muscle Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D054440:Receptors, Ghrelin; D000070584:Tripartite Motif Proteins; D003907:Dexamethasone; C091874:growth hormone-releasing peptide-2; C486691:Fbxo32 protein, mouse; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases