title: Phosphodiesterase (PDE) inhibitor torbafylline (HWA 448) attenuates burn-induced rat skeletal muscle proteolysis through the PDE4/cAMP/EPAC/PI3K/Akt pathway.
abstract: Treatment of rats after burn-injury with the cyclic AMP phosphodiesterase (PDE) inhibitor, torbafylline (also known as HWA 448) significantly reversed changes in rat skeletal muscle proteolysis, PDE4 activity, cAMP concentrations and mRNA expression of TNFα, IL-6, ubiquitin and E3 ligases. Torbafylline also attenuated muscle proteolysis during in vitro incubation, and this effect was blocked by the inhibitor Rp-cAMPS. Moreover, torbafylline significantly increased phospho-Akt levels, and normalized downregulated phospho-FOXO1 and phospho-4E-BP1 in muscle of burn rats. Similarly, torbafylline also normalized phosphorylation levels of Akt and its downstream elements in TNFα+IFNγ treated C2C12 myotubes. Torbafylline enhanced protein levels of exchange protein directly activated by cAMP (Epac) both in skeletal muscle of burn rats and in TNFα+IFNγ treated C2C12 myotubes. Pretreatment with a specific antagonist of PI3K or Epac significantly reversed the inhibitory effects of torbafylline on TNFα+IFNγ-induced MAFbx mRNA expression and protein breakdown in C2C12 myotubes. Torbafylline inhibits burn-induced muscle proteolysis by activating multiple pathways through PDE4/cAMP/Epac/PI3K/Akt.
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA.
authors: Rashika
authors: R
authors: Joshi
authors: Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA.
authors: Nijiati
authors: N
authors: Kadeer
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
authors: Sulaiman
authors: S
authors: Sheriff
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA.
authors: Lou Ann
authors: LA
authors: Friend
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA.
authors: J Howard
authors: JH
authors: James
authors: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Shriners Hospital for Children, 3229 Burnet Avenue, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220, USA. Electronic address: ambi.bala@uc.edu.
authors: Ambikaipakan
authors: A
authors: Balasubramaniam
mesh_terms: D000818:Animals; D002056:Burns; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D010726:Phosphodiesterase Inhibitors; C061298:torbafylline; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C546993:PDE4B protein, rat; D010431:Pentoxifylline
keywords: Burn injury; C2C12 myotubes; Muscle atrophy; PDE4; Signaling pathways; Torbafylline