PPAR[beta]/[delta] Regulates Glucocorticoid- and Sepsis-Induced FOXO1 Activation and Muscle Wasting

• Published in: PloS one Vol. 8; no. 3; p. e59726
• Main Authors: Castillero, Estibaliz, Alamdari, Nima, Aversa, Zaira, Gurav, Aniket, Hasselgren, Per-Olof
• Format: Journal Article
• Language: English
• Published: Public Library of Science 21.03.2013
• Subjects: Dexamethasone; Infection; Proteolysis; Steroids (Organic compounds)
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0059726

FOXO1 is involved in glucocorticoid- and sepsis-induced muscle wasting, in part reflecting regulation of atrogin-1 and MuRF1. Mechanisms influencing FOXO1 expression in muscle wasting are poorly understood. We hypothesized that the transcription factor peroxisome proliferator-activated receptor [beta]/[delta] (PPAR[beta]/[delta]) upregulates muscle FOXO1 expression and activity with a downstream upregulation of atrogin-1 and MuRF1 expression during sepsis and glucocorticoid treatment and that inhibition of PPAR[beta]/[delta] activity can prevent muscle wasting. We found that activation of PPAR[beta]/[delta] in cultured myotubes increased FOXO1 activity, atrogin-1 and MuRF1 expression, protein degradation and myotube atrophy. Treatment of myotubes with dexamethasone increased PPAR[beta]/[delta] expression and activity. Dexamethasone-induced FOXO1 activation and atrogin-1 and MuRF1 expression, protein degradation, and myotube atrophy were inhibited by PPAR[beta]/[delta] blocker or siRNA. Importantly, muscle wasting induced in rats by dexamethasone or sepsis was prevented by treatment with a PPAR[beta]/[delta] inhibitor. The present results suggest that PPAR[beta]/[delta] regulates FOXO1 activation in glucocorticoid- and sepsis-induced muscle wasting and that treatment with a PPAR[beta]/[delta] inhibitor may ameliorate loss of muscle mass in these conditions.