title: Insulin-like effect of the phosphodiesterase type 5 inhibitor tadalafil onto male human skeletal muscle cells.
abstract: BACKGROUND
  Phosphodiesterase type 5 inhibitors (PDE5i), widely used to treat male erectile dysfunction, seem to counteract insulin resistance (IR) in animals and humans. IR, primarily manifest in peripheral tissues and particularly in skeletal muscle, is due to impaired insulin signal transduction. Investigators have been focusing onto intracellular defects responsible for IR to identify suitable pharmacological tools targeted toward the specific defects. Albeit some effects of PDE5i have been reported onto animal muscular tissues or cells, whether and how they might affect metabolic processes directly in human skeletal muscle still remains unclear.
  
  
  OBJECTIVE
  We aimed to investigate in human fetal skeletal muscle cells (Hfsmc) the effect of tadalafil, one of PDE5i, onto some intracellular factors involved in response to insulin, such as ras-raf mitogen activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PKB/Akt), glycogen synthase kinase 3β (GSK-3β), and the transcriptional factor c-Myc; proliferation rate; lactate (lact) and free fatty acid (ffa) release; activity of citrate synthase (CS) and succinate dehydrogenase (SDH), both enzymes of Kreb's cycle; PDE5 gene expression.
  
  
  METHODS
  Western blot analysis, enzyme-linked immunosorbent assay, enzymatic assays, cell count, MTT assay and Real Time PCR were performed in Hfsmc with and without tadalafil.
  
  
  RESULTS
  In Hfsmc tadalafil affected the insulin-related intracellular cascade, by increasing MAPK, PKB/Akt, GSK-3β phosphorylation and c-Myc expression. ffa release and CS activity also significantly increased, with no changes in SDH activity and lact release.
  
  
  CONCLUSIONS
  Tadalafil, like insulin, targeted part of the machinery dedicated to energy management and metabolic control in human skeletal muscle cells.
authors.affiliation: Department of Movement, Human and Health Sciences, Section of Health Sciences, University of Rome "Foro Italico", 00135 Rome, Italy. clara.crescioli@uniroma4.it.
authors.forename: C
authors.initials: C
authors.lastname: Crescioli
authors.forename: N
authors.initials: N
authors.lastname: Sturli
authors.forename: M
authors.initials: M
authors.lastname: Sottili
authors.forename: P
authors.initials: P
authors.lastname: Bonini
authors.forename: A
authors.initials: A
authors.lastname: Lenzi
authors.forename: L
authors.initials: L
authors.lastname: Di Luigi
mesh_terms: D002243:Carbolines / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D000068581:Tadalafil
chemical_list: D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3