1. Muscle-specific microRNA1 (miR1) targets heat shock protein 70 (HSP70) during dexamethasone-mediated atrophy.
- Author
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Kukreti H, Amuthavalli K, Harikumar A, Sathiyamoorthy S, Feng PZ, Anantharaj R, Tan SL, Lokireddy S, Bonala S, Sriram S, McFarlane C, Kambadur R, and Sharma M
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, CHO Cells, Cricetinae, Cricetulus, Dexamethasone pharmacology, Forkhead Box Protein O3, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, HSP70 Heat-Shock Proteins genetics, Mice, Mice, Knockout, MicroRNAs genetics, Muscle Proteins biosynthesis, Muscle Proteins genetics, Muscular Atrophy genetics, Muscular Atrophy pathology, Phosphorylation drug effects, Phosphorylation genetics, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, SKP Cullin F-Box Protein Ligases biosynthesis, SKP Cullin F-Box Protein Ligases genetics, Tripartite Motif Proteins, Ubiquitin-Protein Ligases biosynthesis, Ubiquitin-Protein Ligases genetics, Up-Regulation drug effects, Up-Regulation genetics, Anti-Inflammatory Agents adverse effects, Dexamethasone adverse effects, HSP70 Heat-Shock Proteins metabolism, MicroRNAs metabolism, Models, Biological, Muscular Atrophy chemically induced, Muscular Atrophy metabolism
- 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.
- Published
- 2013
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