Tribbles 3 regulates protein turnover in mouse skeletal muscle

• Published in: Biochemical and biophysical research communications 2017-11, Vol.493 (3), p.1236-1242
• Main Authors: Choi, Ran Hee, McConahay, Abigail, Jeong, Ha-Won, McClellan, Jamie L., Hardee, Justin P., Carson, James A., Hirshman, Michael F., Goodyear, Laurie J., Koh, Ho-Jin
• Format: Article
• Language: English
• Subjects: Animals; Atrophy; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Female; Forkhead Box Protein O1 - metabolism; Forkhead Box Protein O3 - metabolism; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle Proteins - genetics; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiopathology; Protein Biosynthesis - genetics; Protein degradation; Protein synthesis; Proto-Oncogene Proteins c-akt - metabolism; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; SKP Cullin F-Box Protein Ligases - genetics; TOR Serine-Threonine Kinases - metabolism; TRB3
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.09.134

Skeletal muscle atrophy is associated with a disruption in protein turnover involving increased protein degradation and suppressed protein synthesis. Although it has been well studied that the IGF-1/PI3K/Akt pathway plays an essential role in the regulation of the protein turnover, molecule(s) that triggers the change in protein turnover still remains to be elucidated. TRB3 has been shown to inhibit Akt through direct binding. In this study, we hypothesized that TRB3 in mouse skeletal muscle negatively regulates protein turnover via the disruption of Akt and its downstream molecules. Muscle-specific TRB3 transgenic (TRB3TG) mice had decreased muscle mass and fiber size, resulting in impaired muscle function. We also found that protein synthesis rate and signaling molecules, mTOR and S6K1, were significantly reduced in TRB3TG mice, whereas the protein breakdown pathway was significantly activated. In contrast, TRB3 knockout mice showed increased muscle mass and had an increase in protein synthesis rate, but decreases in FoxOs, atrogin-1, and MuRF-1. These findings indicate that TRB3 regulates protein synthesis and breakdown via the Akt/mTOR/FoxO pathways. •Muscle-specific TRB3 transgenic (TRB3TG) mice display smaller muscle mass and fiber size.•TRB3TG mice show decreased protein synthesis rates and signaling compared to WT.•Protein degradation pathway is highly activated in TRB3TG mice.•TRB3 knockout mice have higher muscle mass with increased protein synthesis rates.