CRTC2 Contributes to PGC‐1α Expression in Skeletal Muscle Cells

Muscle wasting associated with chronic diseases has been linked to decreased expression of the transcriptional coactivator PGC‐1α. Overexpression of PGC‐1α can reduce FoxO‐mediated atrogene expression and counter muscle loss. Previous reports indicate that PGC‐1α transcription is regulated by CREB in a process that requires CREB‐regulated transcription coactivator (CRTC2). We recently found that CRTC2 protein is reduced in skeletal muscle of diabetic rats whereas CREB is highly phosphorylated (i.e., activated). Nuclear translocation of CRTC2 is promoted by dephosphorylation via calcineurin (CnA) while nuclear export occurs by phosphorylation via the salt‐inducible kinases (SIK). Our experiments tested the hypothesis that glucocorticoids decrease PGC‐1α expression, in part, by reducing CRTC2 levels in the nucleus. L6 myotubes were treated ± dexamethasone (Dex, 100nM) for 48hrs. Dex decreased PGC‐1α protein and nuclear level of CRTC2. It also decreased nuclear CnA and increased nuclear SIK, supporting the observed reduction in nuclear CRTC2 levels. Over‐expression of CRTC2 increased PGC‐1α protein and mRNA levels. To assess the role of CRTC2 on PGC‐1α transcription, muscle cells were transfected with a PGC‐1α luciferase reporter plasmid (PGC‐1α‐Luc). Over‐expression of CRTC2 increased PGC‐1α‐Luc activity. Dex decreased PGC‐1α‐Luc activity and deletion of the CRE binding site from PGC‐1α‐Luc (PGC‐1α‐DCRE‐Luc) attenuated the response. These data support the interaction of CRTC2 with phospho‐CREB as a mechanism for increasing PGC‐1α expression. Reduced nuclear CRTC2 may contribute to the loss of muscle mass arising during chronic diseases associated with elevated glucocorticoids. Supported by NIH RO1 DK95610, NIH T32 DK007656 and VA Merit X01BX001456