PPARβ/δ regulates glucocorticoid- and sepsis-induced FOXO1 activation and muscle wasting

• Published in: PloS one 2013-03, Vol.8 (3), p.e59726-e59726
• Main Authors: Castillero, Estibaliz, Alamdari, Nima, Aversa, Zaira, Gurav, Aniket, Hasselgren, Per-Olof
• Format: Article
• Language: English
• Subjects: Activation; Animals; Atrophy; Biology; Cell Nucleus - metabolism; Degradation; Dexamethasone; Dexamethasone - pharmacology; Diabetes; Endocrinology; Fatty acids; Forkhead Transcription Factors - metabolism; FOXO1 protein; Genes; Glucocorticoids; Glucocorticoids - metabolism; Glucose; Inhibitors; Insulin resistance; Kinases; Medical schools; Medicine; Metabolism; Muscle Fibers, Skeletal - metabolism; Muscle Proteins - metabolism; Muscles; Muscles - metabolism; Muscular Atrophy - metabolism; Musculoskeletal system; Myotubes; Nerve Tissue Proteins - metabolism; Phosphorylation; PPAR delta - metabolism; PPAR-beta - metabolism; Proteins; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Glucocorticoid - metabolism; RNA, Small Interfering - metabolism; Rodents; Sepsis; Sepsis - metabolism; siRNA; SKP Cullin F-Box Protein Ligases - metabolism; Studies; Surgery; Thiazoles - pharmacology; Transcription factors; Tripartite Motif Proteins; Ubiquitin-Protein Ligases - metabolism; Up-Regulation
• 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 β/δ (PPARβ/δ) 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 PPARβ/δ activity can prevent muscle wasting. We found that activation of PPARβ/δ in cultured myotubes increased FOXO1 activity, atrogin-1 and MuRF1 expression, protein degradation and myotube atrophy. Treatment of myotubes with dexamethasone increased PPARβ/δ expression and activity. Dexamethasone-induced FOXO1 activation and atrogin-1 and MuRF1 expression, protein degradation, and myotube atrophy were inhibited by PPARβ/δ blocker or siRNA. Importantly, muscle wasting induced in rats by dexamethasone or sepsis was prevented by treatment with a PPARβ/δ inhibitor. The present results suggest that PPARβ/δ regulates FOXO1 activation in glucocorticoid- and sepsis-induced muscle wasting and that treatment with a PPARβ/δ inhibitor may ameliorate loss of muscle mass in these conditions.