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MicroRNA 322 Aggravates Dexamethasone-Induced Muscle Atrophy by Targeting IGF1R and INSR
Hongwei Geng1, Qinglong Song2,3, Yunyun Cheng1
1College of Animal Science, Jilin University, Changchun 130062, China.
Abstract:
Dexamethasone (Dex) has been widely used as a potent anti-inflammatory, antishock, and immunosuppressive agent. However, high dose or long-term use of Dex is accompanied by side effects including skeletal muscle atrophy, whose underlying mechanisms remain incompletely understood. A number of microRNAs (miRNAs) have been shown to play key roles in skeletal muscle atrophy. Previous studies showed significantly increased miR-322 expression in Dex-treated C2C12 myotubes. In our study, the glucocorticoid receptor (GR) was required for Dex to increase miR-322 expression in C2C12 myotubes. miR-322 mimic or miR-322 inhibitor was used for regulating the expression of miR-322. Insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (INSR) were identified as target genes of miR-322 using luciferase reporter assays and played key roles in Dex-induced muscle atrophy. miR-322 overexpression promoted atrophy in Dex-treated C2C12 myotubes and the gastrocnemius muscles of mice. Conversely, miR-322 inhibition showed the opposite effects. These data suggested that miR-322 contributes to Dex-induced muscle atrophy via targeting of IGF1R and INSR. Furthermore, miR-322 might be a potential target to counter Dex-induced muscle atrophy. miR-322 inhibition might also represent a therapeutic approach for Dex-induced muscle atrophy.
Insights
Dexamethasone-induced muscle atrophy is linked to increased miR-322. This microRNA targets IGF1R and INSR, promoting muscle wasting. Inhibiting miR-322 may offer a therapeutic strategy against this side effect.
Area of Science:
- Molecular Biology
- Biochemistry
- Physiology
Background:
- Dexamethasone (Dex) is a widely used anti-inflammatory and immunosuppressive drug.
- Long-term or high-dose Dex use can cause skeletal muscle atrophy, but mechanisms are unclear.
- MicroRNAs (miRNAs) are implicated in skeletal muscle atrophy, with miR-322 found to be upregulated by Dex.
Purpose of the Study:
- To investigate the role of miR-322 in Dexamethasone-induced skeletal muscle atrophy.
- To identify the molecular targets of miR-322 involved in this process.
- To explore miR-322 as a potential therapeutic target for mitigating Dex-induced muscle atrophy.
Main Methods:
- Utilized C2C12 myotubes and mouse gastrocnemius muscles.
- Investigated the requirement of the glucocorticoid receptor (GR) for Dex-induced miR-322 upregulation.
- Employed miR-322 mimics and inhibitors to modulate miR-322 expression.
- Used luciferase reporter assays to identify miR-322 target genes, specifically IGF1R and INSR.
Main Results:
- Dex treatment increased miR-322 expression in C2C12 myotubes, dependent on the GR.
- miR-322 directly targets insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (INSR).
- Overexpression of miR-322 exacerbated Dex-induced atrophy in vitro and in vivo, while inhibition ameliorated it.
Conclusions:
- miR-322 plays a critical role in mediating Dexamethasone-induced skeletal muscle atrophy by targeting IGF1R and INSR.
- miR-322 inhibition presents a potential therapeutic strategy to counteract Dex-induced muscle wasting.
- Targeting miR-322 could be a promising approach for managing side effects of Dexamethasone therapy.
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