Phosphodiesterase inhibition increases PGC‐1α in muscle cells (1102.32)

Abstract

Muscle wasting associated with chronic diseases, such as type I diabetes (DM), can be countered by restoring the reduced expression of the transcriptional coactivator PGC‐1α. Previous reports indicate that PGC‐1α transcription can be regulated by CREB in a process that requires nuclear localization of CRTC (CREB‐regulated transcription coactivator). We recently found that CRTC protein is reduced in skeletal muscle of diabetic rats whereas CREB is highly phosphorylated (i.e., activated). Nuclear translocation of CTRC is promoted by dephosphorylation via calcineurin (CnA) whereas nuclear export occurs by phosphorylation via the salt‐inducible kinases (SIK). Inhibition of phosphodiesterases (PDE), which raise cyclic AMP (cAMP) levels, results in increased PGC‐1α mRNA expression. cAMP also inhibits SIK suggesting this pathway may contribute to CRTC localization and thus PGC‐1α activity. Our experiments tested the hypothesis that inhibition of PDE increases the amount of nuclear CRTC and PGC‐1α transcription. Myotubes were transfected with luciferase reporter plasmids (Luc) and treated with the general PDE inhibitor IBMX (250uM) for 6 hours. IBMX increased PGC‐1α‐Luc promoter activity as well as the transcriptional activity of CREB. Deletion of the CRE site in PGC‐1α‐Luc prevents the increase in luciferase activity suggesting IBMX increases PGC‐1α activity via CREB. In addition, protein analysis indicates IBMX increases the level of nuclear CRTC. Together, these data imply that raising cAMP levels by inhibiting PDEs results in increased PGC‐1α transcriptional activity by a mechanism involving CREB and its coactivator, CRTC.Grant Funding Source: Supported by NIH RO1 DK95610, NIH T32 DK007656 and VA Merit X01BX001456