Muscle-specific microRNA1 (miR1) targets heat shock protein 70 (HSP70) during dexamethasone-mediated atrophy
| Autor: | Rengaraj Anantharaj, Ravi Kambadur, Peng Zhao Feng, Sabeera Bonala, Sushmitha Sathiyamoorthy, Sudarsanareddy Lokireddy, Arigela Harikumar, Craig McFarlane, Suan Liang Kelvin Tan, Mridula Sharma, Kottaiswamy Amuthavalli, Himani Kukreti, Sandhya Sriram |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Ubiquitin-Protein Ligases Anti-Inflammatory Agents Muscle Proteins Myostatin CHO Cells Biology Biochemistry Models Biological Dexamethasone Tripartite Motif Proteins Mice Atrophy Glucocorticoid receptor Cricetulus Internal medicine Cricetinae medicine Animals HSP70 Heat-Shock Proteins Phosphorylation Molecular Biology Mice Knockout SKP Cullin F-Box Protein Ligases Myogenesis Forkhead Box Protein O3 Skeletal muscle Forkhead Transcription Factors Molecular Bases of Disease Cell Biology medicine.disease Muscle atrophy Up-Regulation MicroRNAs Muscular Atrophy Endocrinology medicine.anatomical_structure biology.protein FOXO3 medicine.symptom Proto-Oncogene Proteins c-akt hormones hormone substitutes and hormone antagonists |
| Zdroj: | The Journal of biological chemistry. 288(9) |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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