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miR-182 attenuates atrophy-related gene expression by targeting FoxO3 in skeletal muscle
Matthew B Hudson1, Jill A Rahnert2, Bin Zheng2
1Department of Medicine, Renal Division, Emory University, Atlanta, Georgia; mbhudson@emory.edu.
Abstract:
Skeletal muscle atrophy occurs in response to a variety of conditions including chronic kidney disease, diabetes, cancer, and elevated glucocorticoids. MicroRNAs (miR) may play a role in the wasting process. Activation of the forkhead box O3 (FoxO3) transcription factor causes skeletal muscle atrophy in patients, animals, and cultured cells by increasing the expression of components of the ubiquitin-proteasome and autophagy-lysosome proteolytic systems. To identify microRNAs that potentially modulate the atrophy process, an in silico target analysis was performed and miR-182 was predicted to target FoxO3 mRNA. Using a combination of immunoblot analysis, quantitative real-time RT-PCR, and FoxO3 3'-UTR luciferase reporter genes, miR-182 was confirmed to regulate FoxO3 expression in C2C12 myotubes. Transfection of miR-182 into muscle cells decreased FoxO3 mRNA 30% and FoxO3 protein 67% (P < 0.05) and also prevented a glucocorticoid-induced upregulation of multiple FoxO3 gene targets including MAFbx/atrogin-1, autophagy-related protein 12 (ATG12), cathepsin L, and microtubule-associated protein light chain 3 (LC3). Treatment of C2C12 myotubes with dexamethasone (Dex) (1 μM, 6 h) to induce muscle atrophy decreased miR-182 expression by 63% (P < 0.05). Similarly, miR-182 was decreased 44% (P < 0.05) in the gastrocnemius muscle of rats injected with streptozotocin to induce diabetes compared with controls. Finally, miR-182 was present in exosomes isolated from the media of C2C12 myotubes and Dex increased its abundance. These data identify miR-182 as an important regulator of FoxO3 expression that participates in the control of atrophy-inducing genes during catabolic diseases.
Insights
MicroRNA-182 (miR-182) regulates skeletal muscle atrophy by controlling the expression of FoxO3. Decreased miR-182 is linked to muscle wasting in catabolic diseases like diabetes.
Area of Science:
- Molecular Biology
- Cell Biology
- Physiology
Background:
- Skeletal muscle atrophy is a complex process implicated in various diseases.
- MicroRNAs (miRNAs) are emerging as key regulators in cellular processes, including muscle wasting.
- The transcription factor FoxO3 (forkhead box O3) plays a critical role in mediating muscle atrophy by upregulating proteolytic systems.
Purpose of the Study:
- To investigate the role of microRNAs in skeletal muscle atrophy.
- To identify specific microRNAs that target the FoxO3 mRNA.
- To elucidate the regulatory relationship between miR-182 and FoxO3 in the context of muscle atrophy.
Main Methods:
- In silico analysis to predict miRNA targets.
- Utilized C2C12 myotubes for cell culture experiments.
- Employed immunoblot analysis, quantitative real-time RT-PCR, and luciferase reporter assays.
- Induced muscle atrophy using dexamethasone and diabetes model in rats (streptozotocin).
- Exosome isolation and analysis.
Main Results:
- miR-182 was predicted to target FoxO3 mRNA and experimentally confirmed to regulate FoxO3 expression in myotubes.
- Overexpression of miR-182 decreased FoxO3 mRNA and protein levels, and prevented the upregulation of FoxO3 target genes involved in muscle breakdown.
- miR-182 expression was significantly reduced in dexamethasone-treated myotubes and in the muscle of diabetic rats.
- miR-182 was found in exosomes, and its abundance increased with dexamethasone treatment.
Conclusions:
- miR-182 is identified as a crucial regulator of FoxO3 expression in skeletal muscle.
- This microRNA plays a significant role in controlling atrophy-related genes during catabolic conditions.
- miR-182 represents a potential therapeutic target for mitigating skeletal muscle atrophy in diseases like diabetes.
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