title: Muscle-specific expression of the RNA-binding protein Staufen1 induces progressive skeletal muscle atrophy via regulation of phosphatase tensin homolog.
abstract: Converging lines of evidence have now highlighted the key role for post-transcriptional regulation in the neuromuscular system. In particular, several RNA-binding proteins are known to be misregulated in neuromuscular disorders including myotonic dystrophy type 1, spinal muscular atrophy and amyotrophic lateral sclerosis. In this study, we focused on the RNA-binding protein Staufen1, which assumes multiple functions in both skeletal muscle and neurons. Given our previous work that showed a marked increase in Staufen1 expression in various physiological and pathological conditions including denervated muscle, in embryonic and undifferentiated skeletal muscle, in rhabdomyosarcomas as well as in myotonic dystrophy type 1 muscle samples from both mouse models and humans, we investigated the impact of sustained Staufen1 expression in postnatal skeletal muscle. To this end, we generated a skeletal muscle-specific transgenic mouse model using the muscle creatine kinase promoter to drive tissue-specific expression of Staufen1. We report that sustained Staufen1 expression in postnatal skeletal muscle causes a myopathy characterized by significant morphological and functional deficits. These deficits are accompanied by a marked increase in the expression of several atrophy-associated genes and by the negative regulation of PI3K/AKT signaling. We also uncovered that Staufen1 mediates PTEN expression through indirect transcriptional and direct post-transcriptional events thereby providing the first evidence for Staufen1-regulated PTEN expression. Collectively, our data demonstrate that Staufen1 is a novel atrophy-associated gene, and highlight its potential as a biomarker and therapeutic target for neuromuscular disorders and conditions.
authors.affiliation: Department of Cellular and Molecular Medicine, Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Tara E
authors.initials: TE
authors.lastname: Crawford Parks
authors.affiliation: Department of Cellular and Molecular Medicine, Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Ravel-Chapuis
authors.affiliation: Department of Cellular and Molecular Medicine, Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Emma
authors.initials: E
authors.lastname: Bondy-Chorney
authors.affiliation: Department of Cellular and Molecular Medicine, Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Renaud
authors.affiliation: Department of Cellular and Molecular Medicine, Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Côté
authors.affiliation: Department of Cellular and Molecular Medicine, Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Jasmin
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D012313:RNA / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000070876:Tensins
chemical_list: D016601:RNA-Binding Proteins; C492187:Stau1 protein, mouse; D000070876:Tensins; D012313:RNA; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse