title: Muscle-specific microRNA1 (miR1) targets heat shock protein 70 (HSP70) during dexamethasone-mediated atrophy.
abstract: High doses of dexamethasone (Dex) or myostatin (Mstn) induce severe atrophy of skeletal muscle. Here we show a novel microRNA1 (miR1)-mediated mechanism through which Dex promotes skeletal muscle atrophy. Using both C2C12 myotubes and mouse models of Dex-induced atrophy we show that Dex induces miR1 expression through glucocorticoid receptor (GR). We further show that Mstn treatment facilitates GR nuclear translocation and thereby induces miR1 expression. Inhibition of miR1 in C2C12 myotubes attenuated the Dex-induced increase in atrophy-related proteins confirming a role for miR1 in atrophy. Analysis of miR1 targets revealed that HSP70 is regulated by miR1 during atrophy. Our results demonstrate that increased miR1 during atrophy reduced HSP70 levels, which resulted in decreased phosphorylation of AKT, as HSP70 binds to and protects phosphorylation of AKT. We further show that loss of pAKT leads to decreased phosphorylation, and thus, enhanced activation of FOXO3, up-regulation of MuRF1 and Atrogin-1, and progression of skeletal muscle atrophy. Based on these results, we propose a model whereby Dex- and Mstn-mediated atrophic signals are integrated through miR1, which then either directly or indirectly, inhibits the proteins involved in providing protection against atrophy.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive MD7, Singapore 117597.
authors.forename: Himani
authors.initials: H
authors.lastname: Kukreti
authors.forename: Kottaiswamy
authors.initials: K
authors.lastname: Amuthavalli
authors.forename: Arigela
authors.initials: A
authors.lastname: Harikumar
authors.forename: Sushmitha
authors.initials: S
authors.lastname: Sathiyamoorthy
authors.forename: Peng Zhao
authors.initials: PZ
authors.lastname: Feng
authors.forename: Rengaraj
authors.initials: R
authors.lastname: Anantharaj
authors.forename: Suan Liang Kelvin
authors.initials: SL
authors.lastname: Tan
authors.forename: Sudarsanareddy
authors.initials: S
authors.lastname: Lokireddy
authors.forename: Sabeera
authors.initials: S
authors.lastname: Bonala
authors.forename: Sandhya
authors.initials: S
authors.lastname: Sriram
authors.forename: Craig
authors.initials: C
authors.lastname: McFarlane
authors.forename: Ravi
authors.initials: R
authors.lastname: Kambadur
authors.forename: Mridula
authors.initials: M
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003907:Dexamethasone / Q000009:adverse effects* / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D018840:HSP70 Heat-Shock Proteins; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D003907:Dexamethasone; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt