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Guanidinoacetic Acid Regulates Myogenic Differentiation and Muscle Growth Through miR-133a-3p and miR-1a-3p Co-mediated Akt/mTOR/S6K Signaling Pathway.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2018 Sep 19; Vol. 19 (9). Date of Electronic Publication: 2018 Sep 19. - Publication Year :
- 2018
-
Abstract
- Guanidinoacetic acid (GAA), an amino acid derivative that is endogenous to animal tissues including muscle and nerve, has been reported to enhance muscular performance. MicroRNA (miRNA) is a post-transcriptional regulator that plays a key role in nutrient-mediated myogenesis. However, the effects of GAA on myogenic differentiation and skeletal muscle growth, and the potential regulatory mechanisms of miRNA in these processes have not been elucidated. In this study, we investigated the effects of GAA on proliferation, differentiation, and growth in C2C12 cells and mice. The results showed that GAA markedly inhibited the proliferation of myoblasts, along with the down-regulation of cyclin D1 ( CCND1 ) and cyclin dependent kinase 4 ( CDK4 ) mRNA expression, and the upregulation of cyclin dependent kinase inhibitor 1A ( P21 ) mRNA expression. We also demonstrated that GAA treatment stimulated myogenic differentiation 1 ( MyoD ) and myogenin ( MyoG ) mRNA expression, resulting in an increase in the myotube fusion rate. Meanwhile, GAA supplementation promoted myotube growth through increase in total myosin heavy chain (MyHC) protein level, myotubes thickness and gastrocnemius muscle cross-sectional area. Furthermore, small RNA sequencing revealed that a total of eight miRNAs, including miR-133a-3p and miR-1a-3p cluster, showed differential expression after GAA supplementation. To further study the function of miR-133a-3p and miR-1a-3p in GAA-induced skeletal muscle growth, we transfected miR-133a-3p and miR-1a-3p mimics into myotube, which also induced muscle growth. Through bioinformatics and a dual-luciferase reporter system, the target genes of miR-133a-3p and miR-1a-3p were determined. These two miRNAs were shown to modulate the Akt/mTOR/S6K signaling pathway by restraining target gene expression. Taken together, these findings suggest that GAA supplementation can promote myoblast differentiation and skeletal muscle growth through miR-133a-3p- and miR-1a-3p-induced activation of the AKT/mTOR/S6K signaling pathway.
- Subjects :
- Animals
Cell Line
Cyclin D1 genetics
Cyclin D1 metabolism
Cyclin-Dependent Kinase 4 genetics
Cyclin-Dependent Kinase 4 metabolism
Cyclin-Dependent Kinase Inhibitor p21 genetics
Cyclin-Dependent Kinase Inhibitor p21 metabolism
Glycine pharmacology
Male
Mice
MicroRNAs metabolism
MyoD Protein genetics
MyoD Protein metabolism
Myoblasts cytology
Myoblasts drug effects
Myoblasts metabolism
Myogenin genetics
Myogenin metabolism
Proto-Oncogene Proteins c-akt genetics
Ribosomal Protein S6 Kinases genetics
Ribosomal Protein S6 Kinases metabolism
TOR Serine-Threonine Kinases genetics
Glycine analogs & derivatives
MicroRNAs genetics
Muscle Development
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction
TOR Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 19
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 30235878
- Full Text :
- https://doi.org/10.3390/ijms19092837