Figure 11.

Proposed scheme for GSK773 molecular mechanisms. GSK773 is a direct and specific activator of AMPK. Its binding to the β1 subunit phosphorylates and activates AMPK. GSK773 induces p38 MAPK phosphorylation. GSK773 also induces an increase of ROS levels, which might participate to AMPK and p38 phosphorylation. Like AMPK (cf Figure 9), p38 MAPK can also directly phosphorylate PGC-1α, and several transcription factors such as MEF2 and ATF2, whose binding sites are present on PGC-1α promoter. These mechanisms might account for the GSK773-induced increase of PGC-1α transcription and protein levels. PGC-1α might then upregulate the transcription of CPT2, Tfam and MYH7, which encodes myosin heavy chain I (MHCI) expressed in oxidative slow twitch fibers. Finally, the coordinated increase of PGC-1α, Tfam, FAO proteins and certainly nuclear and mitochondrial encoded RC proteins are consistent with the mitochondrial biogenesis induced by GSK773.