title: Urocortins improve dystrophic skeletal muscle structure and function through both PKA- and Epac-dependent pathways.
abstract: In Duchenne muscular dystrophy, the absence of dystrophin causes progressive muscle wasting and premature death. Excessive calcium influx is thought to initiate the pathogenic cascade, resulting in muscle cell death. Urocortins (Ucns) have protected muscle in several experimental paradigms. Herein, we demonstrate that daily s.c. injections of either Ucn 1 or Ucn 2 to 3-week-old dystrophic mdx(5Cv) mice for 2 weeks increased skeletal muscle mass and normalized plasma creatine kinase activity. Histological examination showed that Ucns remarkably reduced necrosis in the diaphragm and slow- and fast-twitch muscles. Ucns improved muscle resistance to mechanical stress provoked by repetitive tetanizations. Ucn 2 treatment resulted in faster kinetics of contraction and relaxation and a rightward shift of the force-frequency curve, suggesting improved calcium homeostasis. Ucn 2 decreased calcium influx into freshly isolated dystrophic muscles. Pharmacological manipulation demonstrated that the mechanism involved the corticotropin-releasing factor type 2 receptor, cAMP elevation, and activation of both protein kinase A and the cAMP-binding protein Epac. Moreover, both STIM1, the calcium sensor that initiates the assembly of store-operated channels, and the calcium-independent phospholipase A(2) that activates these channels were reduced in dystrophic muscle by Ucn 2. Altogether, our results demonstrate the high potency of Ucns for improving dystrophic muscle structure and function, suggesting that these peptides may be considered for treatment of Duchenne muscular dystrophy.
authors.affiliation: Laboratory of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Reutenauer-Patte
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Boittin
authors.forename: Ophélie
authors.initials: O
authors.lastname: Patthey-Vuadens
authors.forename: Urs T
authors.initials: UT
authors.lastname: Ruegg
authors.forename: Olivier M
authors.initials: OM
authors.lastname: Dorchies
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D054522:Group VI Phospholipases A2 / Q000378:metabolism; D007271:Injections, Intradermal; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D053580:Muscle Strength / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1; D054832:Urocortins / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
chemical_list: D015220:Calcium Channels; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D018019:Receptors, Corticotropin-Releasing Hormone; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D054832:Urocortins; D020126:Brefeldin A; D000099052:CRF Receptor, Type 1; D004917:Erythromycin; C057513:erythromycin propionate-N-acetylcysteinate; D017868:Cyclic AMP-Dependent Protein Kinases; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D002118:Calcium; D000111:Acetylcysteine