PED/PEA-15 induces autophagy and mediates TGF-beta1 effect on muscle cell differentiation

• Published in: Cell death and differentiation 2012-07, Vol.19 (7), p.1127-1138
• Main Authors: Iovino, S, Oriente, F, Botta, G, Cabaro, S, Iovane, V, Paciello, O, Viggiano, D, Perruolo, G, Formisano, P, Beguinot, F
• Format: Article
• Language: English
• Subjects: 631/136/142; 631/45/127/1219; 631/80/39; 692/698/1671/1668/1973; Adenine - analogs & derivatives; Adenine - pharmacology; Animals; Apoptosis; Apoptosis Regulatory Proteins; Astrocytes - cytology; Astrocytes - metabolism; Autophagy; Autophagy - drug effects; Biochemistry; Biomedical and Life Sciences; Carboxylic Ester Hydrolases - metabolism; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line; Diabetes; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; Genes; Growth factors; Life Sciences; Metabolism; Mice; Mice, Transgenic; Microtubule-Associated Proteins - metabolism; Molecular biology; Muscle Development; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Musculoskeletal system; Myoblasts - cytology; Myoblasts - metabolism; Myogenesis; Original Paper; Pathology; Phosphoproteins - antagonists & inhibitors; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Proteins; RNA Interference; RNA, Small Interfering - metabolism; Stem Cells; Transforming Growth Factor beta1 - pharmacology
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2011.201

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 .