title: The utrophin gene is transcriptionally up-regulated in regenerating muscle.
abstract: The utrophin gene codes for a large cytoskeletal protein closely related to dystrophin, the gene mutated in Duchenne's muscular dystrophy. Although utrophin could functionally substitute for dystrophin, in Duchenne's muscular dystrophy patients it did not compensate for the absence of dystrophin because in adult muscle utrophin was poorly expressed and limited to subsynaptic nuclei. However, increased levels of utrophin have been observed in regenerated muscles fibers suggesting that utrophin up-regulation in muscle is feasible. We observed that utrophin mRNA was transiently up-regulated at early time points after muscle injury with a peak already 24 h after muscle damage and utrophin induction in activated satellite cells before fusion into young regenerated fibers. Injection of utrophin lacZ constructs into regenerating muscle demonstrated that the utrophin upstream promoter under the control of its intronic enhancer activated the transcription that leads to the expression of the reporter gene in the newly formed fibers, which was not limited to neuromuscular junctions. Utrophin enhancer activity was dependent on an AP-1 site, and in satellite cells of regenerating muscle the AP-1 factors Fra1, Fra2, and JunD were strongly induced. These results establish that utrophin was induced in adult muscle independently from neuromuscular junctions and suggest that growth factors and cytokines that mediate the muscle repair up-regulate utrophin transcription.
authors.affiliation: Dipartimento di Biologia Molecolare, Università degli Studi di Siena, via Fiorentina 1-53100 Siena, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Galvagni
authors.forename: Marcello
authors.initials: M
authors.lastname: Cantini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliviero
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004247:DNA; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009132:Muscles / Q000502:physiology*; D012038:Regeneration; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic; D015854:Up-Regulation; D049411:Utrophin
chemical_list: D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C483600:Utrn protein, mouse; D049411:Utrophin; D004247:DNA