title: Activation of p38 signaling increases utrophin A expression in skeletal muscle via the RNA-binding protein KSRP and inhibition of AU-rich element-mediated mRNA decay: implications for novel DMD therapeutics.
abstract: Several therapeutic approaches are currently being developed for Duchenne muscular dystrophy (DMD) including upregulating the levels of endogenous utrophin A in dystrophic fibers. Here, we examined the role of post-transcriptional mechanisms in controlling utrophin A expression in skeletal muscle. We show that activation of p38 leads to an increase in utrophin A independently of a transcriptional induction. Rather, p38 controls the levels of utrophin A mRNA by extending the half-life of transcripts via AU-rich elements (AREs). This mechanism critically depends on a decrease in the functional availability of KSRP, an RNA-binding protein known to promote decay of ARE-containing transcripts. In vitro and in vivo binding studies revealed that KSRP interacts with specific AREs located within the utrophin A 3' UTR. Electroporation experiments to knockdown KSRP led to an increase in utrophin A in wild-type and mdx mouse muscles. In pre-clinical studies, treatment of mdx mice with heparin, an activator of p38, causes a pronounced increase in utrophin A in diaphragm muscle fibers. Together, these studies identify a pathway that culminates in the post-transcriptional regulation of utrophin A through increases in mRNA stability. Furthermore, our results constitute proof-of-principle showing that pharmacological activation of p38 may prove beneficial as a novel therapeutic approach for DMD.
authors.affiliation: Faculty of Medicine, Department of Cellular and Molecular Medicine and Centre for Neuromuscular Disease, University of Ottawa, ON, Canada K1H 8M5.
authors.forename: Adel
authors.initials: A
authors.lastname: Amirouche
authors.forename: Helina
authors.initials: H
authors.lastname: Tadesse
authors.forename: John A
authors.initials: JA
authors.lastname: Lunde
authors.forename: Guy
authors.initials: G
authors.lastname: Bélanger
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Côté
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Jasmin
mesh_terms: D020413:3' Untranslated Regions; D063307:AU Rich Elements; D000818:Animals; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism*; D009137:Muscular Dystrophy, Animal; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D049411:Utrophin / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C105789:KHSRP protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D049411:Utrophin; D006493:Heparin; D048051:p38 Mitogen-Activated Protein Kinases