title: Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy.
abstract: Numerous therapeutic approaches for Duchenne and Becker Muscular Dystrophy (DMD and BMD), the most common X-linked muscle degenerative disease, have been proposed. So far, the only one showing a clear beneficial effect is the use of corticosteroids. Recent evidence indicates an improvement of dystrophic cardiac and skeletal muscles in the presence of sustained cGMP levels secondary to a blocking of their degradation by phosphodiesterase five (PDE5). Due to these data, we performed a study to investigate the effect of the specific PDE5 inhibitor, tadalafil, on dystrophic skeletal muscle function. Chronic pharmacological treatment with tadalafil has been carried out in mdx mice. Behavioral and physiological tests, as well as histological and biochemical analyses, confirmed the efficacy of the therapy. We then performed a microarray-based genomic analysis to assess the pattern of gene expression in muscle samples obtained from the different cohorts of animals treated with tadalafil. This scrutiny allowed us to identify several classes of modulated genes. Our results show that PDE5 inhibition can ameliorate dystrophy by acting at different levels. Tadalafil can lead to (1) increased lipid metabolism; (2) a switch towards slow oxidative fibers driven by the up-regulation of PGC-1α; (3) an increased protein synthesis efficiency; (4) a better actin network organization at Z-disk.
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: De Arcangelis
authors.affiliation: CNR-IBCN, Rome, Italy.
authors.forename: Georgios
authors.initials: G
authors.lastname: Strimpakos
authors.affiliation: CNR-IBCN, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gabanella
authors.affiliation: CNR-IBPM, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Corbi
authors.affiliation: CNR-IBCN, Rome, Italy.
authors.forename: Siro
authors.initials: S
authors.lastname: Luvisetto
authors.affiliation: National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Magrelli
authors.affiliation: CNR-IBPM, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Onori
authors.affiliation: CNR-IBPM, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Passananti
authors.affiliation: CNR-IBPM, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Pisani
authors.affiliation: CarMen Laboratory (INSERM 1060, INRA 1362, INSA), University of Lyon, Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rome
authors.affiliation: CNR-IBCN, Rome, Italy.|European Brain Research Institute, Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Severini
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Naro
authors.affiliation: CNR-IBCN, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattei
authors.affiliation: CNR-IBCN, Rome, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Di Certo
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Monaco
mesh_terms: D000818:Animals; D005260:Female; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D000068581:Tadalafil / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058986:Phosphodiesterase 5 Inhibitors; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D000068581:Tadalafil