title: Involvement of microRNAs in the regulation of muscle wasting during catabolic conditions.
abstract: Loss of muscle proteins and the consequent weakness has important clinical consequences in diseases such as cancer, diabetes, chronic heart failure, and in aging. In fact, excessive proteolysis causes cachexia, accelerates disease progression, and worsens life expectancy. Muscle atrophy involves a common pattern of transcriptional changes in a small subset of genes named atrophy-related genes or atrogenes. Whether microRNAs play a role in the atrophy program and muscle loss is debated. To understand the involvement of miRNAs in atrophy we performed miRNA expression profiling of mouse muscles under wasting conditions such as fasting, denervation, diabetes, and cancer cachexia. We found that the miRNA signature is peculiar of each catabolic condition. We then focused on denervation and we revealed that changes in transcripts and microRNAs expression did not occur simultaneously but were shifted. Indeed, whereas transcriptional control of the atrophy-related genes peaks at 3 days, changes of miRNA expression maximized at 7 days after denervation. Among the different miRNAs, microRNA-206 and -21 were the most induced in denervated muscles. We characterized their pattern of expression and defined their role in muscle homeostasis. Indeed, in vivo gain and loss of function experiments revealed that miRNA-206 and miRNA-21 were sufficient and required for atrophy program. In silico and in vivo approaches identified transcription factor YY1 and the translational initiator factor eIF4E3 as downstream targets of these miRNAs. Thus miRNAs are important for fine-tuning the atrophy program and their modulation can be a novel potential therapeutic approach to counteract muscle loss and weakness in catabolic conditions.
authors.affiliation: From the Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy, the Ph.D. Programme in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Soares
authors.affiliation: the Department of Biology and CRIBI Biotechnology Centre, University of Padova, 35121 Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cagnin
authors.affiliation: the Department of Biology and CRIBI Biotechnology Centre, University of Padova, 35121 Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Chemello
authors.affiliation: the Department of Biology and CRIBI Biotechnology Centre, University of Padova, 35121 Padova, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Silvestrin
authors.affiliation: the DAHFMO-Unit of Histology and Medical Embryology, Sapienza University, 00161 Roma, Italy, and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Musaro
authors.affiliation: the Department of Biology and CRIBI Biotechnology Centre, University of Padova, 35121 Padova, Italy, cristiano.depitta@unipd.it.
authors.forename: Cristiano
authors.initials: C
authors.lastname: De Pitta
authors.affiliation: the Department of Biology and CRIBI Biotechnology Centre, University of Padova, 35121 Padova, Italy, gerolamo.lanfranchi@unipd.it.
authors.forename: Gerolamo
authors.initials: G
authors.lastname: Lanfranchi
authors.affiliation: From the Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy, the Department of Biomedical Sciences and the Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35121 Padova, Italy, the Telethon Institute of Genetics and Medicine (TIGEM), 80131 Napoli, Italy marco.sandri@unipd.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002100:Cachexia / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism; D009133:Muscular Atrophy / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D013217:Starvation / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D039561:Eukaryotic Initiation Factor-4E; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse
keywords: Gene Expression; MicroRNA (miRNA); Muscle; Muscle Atrophy; Pathology; Protein Degradation; Signal Transduction; Skeletal Muscle; Transcription