title: PED/PEA-15 induces autophagy and mediates TGF-beta1 effect on muscle cell differentiation.
abstract: TGF-beta1 has been shown to induce autophagy in certain cells but whether and how this action is exerted in muscle and whether this activity relates to TGF-beta1 control of muscle cell differentiation remains unknown. Here, we show that expression of the autophagy-promoting protein phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) progressively declines during L6 and C2C12 skeletal muscle cell differentiation. PED/PEA-15 underwent rapid induction upon TGF-beta1 exposure of L6 and C2C12 myoblasts, accompanied by impaired differentiation into mature myotubes. TGF-beta1 also induced autophagy in the L6 and C2C12 cells through a PP2A/FoxO1-mediated mechanism. Both the TGF-beta1 effect on differentiation and that on autophagy were blocked by specific PED/PEA-15 ShRNAs. Myoblasts stably overexpressing PED/PEA-15 did not differentiate and showed markedly enhanced autophagy. In these same cells, the autophagy inhibitor 3-methyladenine rescued TGF-beta1 effect on both autophagy and myogenesis, indicating that PED/PEA-15 mediates TGF-beta1 effects in muscle. Muscles from transgenic mice overexpressing PED/PEA-15 featured a significant number of atrophic fibers, accompanied by increased light chain 3 (LC3)II to LC3I ratio and reduced PP2A/FoxO1 phosphorylation. Interestingly, these mice showed significantly impaired locomotor activity compared with their non-transgenic littermates. TGF-beta1 causes transcriptional upregulation of the autophagy-promoting gene PED/PEA-15, which in turn is capable to induce atrophic responses in skeletal muscle in vivo.
authors.affiliation: Department of Cellular and Molecular Biology and Pathology, University of Naples Federico II, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Iovino
authors.forename: F
authors.initials: F
authors.lastname: Oriente
authors.forename: G
authors.initials: G
authors.lastname: Botta
authors.forename: S
authors.initials: S
authors.lastname: Cabaro
authors.forename: V
authors.initials: V
authors.lastname: Iovane
authors.forename: O
authors.initials: O
authors.lastname: Paciello
authors.forename: D
authors.initials: D
authors.lastname: Viggiano
authors.forename: G
authors.initials: G
authors.lastname: Perruolo
authors.forename: P
authors.initials: P
authors.lastname: Formisano
authors.forename: F
authors.initials: F
authors.lastname: Beguinot
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002460:Cell Line; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C490444:Pea15 protein, mouse; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; C025946:3-methyladenine; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; D000225:Adenine