Over-expression of PRAS40 enhances insulin sensitivity in skeletal muscle

• Published in: Archives of physiology and biochemistry 2014-05, Vol.120 (2), p.64-72
• Main Authors: Wiza, Claudia, Chadt, Alexandra, Blumensatt, Marcel, Kanzleiter, Timo, Herzfeld De Wiza, Daniella, Horrighs, Angelika, Mueller, Heidi, Nascimento, Emmani B.M., Schürmann, Annette, Al-Hasani, Hadi, Ouwens, D. Margriet
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adolescent; Adult; Akt; Amino Acid Substitution; Animals; Gene Expression; Humans; Hyperinsulinism - physiopathology; Insulin - pharmacology; Insulin Resistance - genetics; insulin sensitivity; IRS1; Male; Mechanistic Target of Rapamycin Complex 1; Mice; mTORC1; Multiprotein Complexes - metabolism; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Phosphorylation - drug effects; PRAS40; proteasome; Proteasome Endopeptidase Complex - metabolism; Proto-Oncogene Proteins c-akt - chemistry; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1381-3455; 1744-4160
• DOI: 10.3109/13813455.2014.894076

Abstract Context: Silencing proline-rich Akt substrate of 40-kDa (PRAS40) impairs insulin signalling in skeletal muscle. Objective: This study assessed the effects of over-expressing wild type or mutant AAA-PRAS40, in which the major phosphorylation sites and mTORC1-binding site were mutated, on insulin signalling in skeletal muscle. Results: Over-expression of WT-PRAS40, but not AAA-PRAS40, impaired the insulin-mediated activation of the mTORC1-pathway in human skeletal muscle cells (hSkMC). However, insulin-mediated Akt-phosphorylation was increased upon over-expression of WT-PRAS40 both in hSkMC and mouse skeletal muscle. Also over-expression of AAA-PRAS40 had an insulin-sensitizing effect, although to a lesser extent as WT-PRAS40. The insulin-sensitizing effect associated with increased IRS1 protein abundance and inhibition of proteasome activity. Finally, over-expression of WT-PRAS40 reversed hyperinsulinemia-induced insulin resistance. Conclusion: This study identifies PRAS40 as a regulator of insulin sensitivity in hSkMC. In contrast to the mTORC1-pathway, the insulin-sensitizing action of PRAS40 occurs independent of binding of PRAS40 to the mTORC1-complex.