title: Sepsis and glucocorticoids downregulate the expression of the nuclear cofactor PGC-1beta in skeletal muscle.
abstract: 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 receptor-γ coactivator (PGC)-1β and that PGC-1β may be a repressor of the atrogin-1 and MuRF1 genes. The influence of other muscle-wasting conditions on the expression of PGC-1β is not known. We tested the influence of sepsis and glucocorticoids on PGC-1β and examined the potential link between downregulated PGC-1β 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-1β 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-1β 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-1β small interfering RNA (siRNA) resulted in downregulated PGC-1β expression and increased protein degradation. Taken together, our results suggest that sepsis- and glucocorticoid-induced muscle wasting may, at least in part, be regulated by decreased expression of the nuclear cofactor PGC-1β.
authors.affiliation: Departmentof Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 2215, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Menconi
authors.forename: Zoltan P
authors.initials: ZP
authors.lastname: Arany
authors.forename: Nima
authors.initials: N
authors.lastname: Alamdari
authors.forename: Zaira
authors.initials: Z
authors.lastname: Aversa
authors.forename: Patricia
authors.initials: P
authors.lastname: Gonnella
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Neal
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Smith
authors.forename: Steven
authors.initials: S
authors.lastname: Tizio
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Hasselgren
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000737:chemistry / Q000235:genetics; D018805:Sepsis / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases