title: Phosphodiesterase-4 inhibition reduces proteolysis and atrogenes expression in rat skeletal muscles.
abstract: Phosphodiesterase (PDE) inhibition reduces skeletal muscle atrophy, but the underlying molecular mechanism remains unclear. We used microdialysis to investigate the effects of different PDE inhibitors on interstitial tyrosine concentration as well as proteolytic activity and atrogenes expression in isolated rat muscle. Rolipram, a PDE-4-selective inhibitor, reduced the interstitial tyrosine concentration and rates of muscle protein degradation. The rolipram-induced muscle cAMP increase was accompanied by a decrease in ubiquitin-proteasome system (UPS) activity and atrogin-1 mRNA, a ubiquitin-ligase involved in muscle atrophy. This effect was not associated with Akt phosphorylation but was partially blocked by a protein kinase A inhibitor. Fasting increased atrogin-1, MuRF-1 and LC3b expression, and these effects were markedly suppressed by rolipram. Our data suggest that activation of cAMP signaling by PDE-4 blockade leads to inhibition of UPS activity and atrogenes expression independently of Akt. These findings are important for identifying novel approaches to attenuate muscle atrophy.
authors: Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, SP, Brazil.
authors: Eduardo C
authors: EC
authors: Lira
authors: Dawit A P
authors: DA
authors: Gonçalves
authors: Lucas T
authors: LT
authors: Parreiras-E-Silva
authors: Neusa M
authors: NM
authors: Zanon
authors: Isis C
authors: IC
authors: Kettelhut
authors: Luiz C C
authors: LC
authors: Navegantes
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D023421:Models, Animal; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram / Q000494:pharmacology*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D014443:Tyrosine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D008869:Microtubule-Associated Proteins; D009124:Muscle Proteins; D058988:Phosphodiesterase 4 Inhibitors; D046988:Proteasome Endopeptidase Complex; D051057:Proto-Oncogene Proteins c-akt; D020889:Rolipram; D044843:SKP Cullin F-Box Protein Ligases; D000070584:Tripartite Motif Proteins; D014443:Tyrosine; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C502186:GABARAP protein, rat; C526109:Anxa3 protein, rat; C486692:Fbxo32 protein, rat; C499086:Trim63 protein, rat