title: PPARβ/δ regulates glucocorticoid- and sepsis-induced FOXO1 activation and muscle wasting.
abstract: 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.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Castillero
authors.forename: Nima
authors.initials: N
authors.lastname: Alamdari
authors.forename: Zaira
authors.initials: Z
authors.lastname: Aversa
authors.forename: Aniket
authors.initials: A
authors.lastname: Gurav
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Hasselgren
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation; D000071161:Forkhead Box Protein O1; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D003907:Dexamethasone; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D047494:PPAR delta; D048068:PPAR-beta; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D044843:SKP Cullin F-Box Protein Ligases; D013844:Thiazoles; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C486692:Fbxo32 protein, rat; C499086:Trim63 protein, rat
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