Sepsis and glucocorticoids downregulate the expression of the nuclear cofactor PGC-1 in skeletal muscle

Menconi MJ, Arany ZP, Alamdari N, Aversa Z, Gonnella P, O’Neal P, Smith IJ, Tizio S, Hasselgren P. Sepsis and glucocorticoids downregulate the expression of the nuclear cofactor PGC-1 in skeletal muscle. Am J Physiol Endocrinol Metab 299: E533–E543, 2010. First published July 20, 2010; doi:10.1152/ajpendo.00596.2009.—Muscle wasting during sepsis is at least in part regulated by glucocorticoids and is associated with increased transcription of genes encoding the ubiquitin ligases atrogin-1 and muscle-specific RING-finger protein-1 (MuRF1). Recent studies suggest that muscle atrophy caused by denervation is associated with reduced expression of the nuclear cofactor peroxisome proliferator-activated receptorcoactivator (PGC)-1 and that PGC-1 may be a repressor of the atrogin-1 and MuRF1 genes. The influence of other muscle-wasting conditions on the expression of PGC-1 is not known. We tested the influence of sepsis and glucocorticoids on PGC-1 and examined the potential link between downregulated PGC-1 expression and upregulated atrogin-1 and MuRF1 expression in skeletal muscle. Sepsis in rats and mice and treatment with dexamethasone resulted in downregulated expression of PGC-1 and increased expression of atrogin-1 and MuRF1 in the fast-twitch extensor digitorum longus muscle, with less pronounced changes in the slow-twitch soleus muscle. In additional experiments, adenoviral gene transfer of PGC-1 into cultured C2C12 myotubes resulted in a dose-dependent decrease in atrogin-1 and MuRF1 mRNA levels. Treatment of cultured C2C12 myotubes with dexamethasone or PGC-1 small interfering RNA (siRNA) resulted in downregulated PGC-1 expression and increased protein degradation. Taken together, our results suggest that sepsisand glucocorticoid-induced muscle wasting may, at least in part, be regulated by decreased expression of the nuclear cofactor PGC-1 .