Effects of PGC‐1α Overexpression on Glucocorticoid‐induced Atrophy Signaling in C 2 C 12 Muscle Cells

Muscle wasting (atrophy) is a debilitating consequence of many catabolic conditions and has been linked to decreased expression of the transcriptional coactivator PGC‐1α. In some models of atrophy, overexpression of PGC‐1α attenuates muscle loss, in part, by reducing FoxO‐mediated atrophy gene expression. FoxOs are transcription factors regulated primarily by phosphorylation via Akt. Previous studies indicate that activation of Akt prevents downstream FoxO signaling during atrophy and that overexpression of PGC‐1α increases phosphorylation (i.e. inhibition) of FoxO proteins. The goal of this study was to determine whether increasing PGC‐1α protein preserves Akt phosphorylation using two in vitro models of atrophy, starvation and glucocorticoid treatment. C 2 C 12 myotubes were infected with an adenovirus encoding GFP (control) or PGC‐1α followed by incubation in control differentiation media (DMEM + 2% horse serum), serum‐free DMEM (SF) to induce starvation, or differentiation media with the synthetic glucocorticoid, dexamethasone (Dex, 1uM), for 24h. Infection of cells with the PGC‐1α adenovirus increased PGC‐1α mRNA and protein and augmented Akt phosphorylation. In GFP‐expressing myotubes, SF reduced PGC‐1α protein and Akt phosphorylation and overexpression of PGC‐1α attenuated the starvation response. Dex did not alter PGC‐1α protein or Akt phosphorylation, however, it increased the FoxO target gene, Atrogin‐1. In addition, overexpression of PGC‐1α increased PGC‐1α protein in Dex‐treated cells and attenuated the increase in Atrogin‐1. These data suggest that maintenance of Akt phosphorylation may contribute to the protective effect of PGC‐1α. Furthermore, they underscore the role of PGC‐1α in the preservation of muscle protein during glucocorticoid‐mediated atrophy. Support or Funding Information Supported by NIH RO1 DK95610, NIH T32 DK007656 and VA Merit I01BX001456