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.
Highlights
Dexamethasone (Dex) is an effective synthetic glucocorticoid
Immunofluorescent staining for myosin heavy chain (MyHC) showed the shape of C2C12 myotubes and Dex reduced the diameter of the C2C12 myotubes (Figure 1A)
We investigated whether glucocorticoid receptor (GR) was necessary for Dex to increase the miR-322 expression in C2C12 myotubes
Summary
Dexamethasone (Dex) is an effective synthetic glucocorticoid. And it is commonly used as a therapeutic agent due to its potent anti-inflammatory, antishock, and immunosuppressive functions [1,2]. Previous studies have shown that Dex exhibits direct effects on decreasing protein synthesis and increasing protein catabolism, thereby leading to muscle atrophy [7,8]. A decrease in miR-23a results in increased translation of TRIM63/MuRF-1 and FBXO32/Atrogin-1, whereas miR-23a overexpression protects muscles from glucocorticoid-induced skeletal muscle atrophy [20,21]. The results showed significantly increased miR-322 expression in Dex-treated C2C12 myotubes [22]. A previous study suggested that miR-322 targeted IGF1R and INSR to regulate the signaling pathway involved in mitochondrial function and fatty acid oxidation in the heart of mice [24]. We investigated the effects of miR-322 on muscle atrophy in Dex-treated C2C12 myotubes and identified the target genes of miR-322. We investigated the effects of miR-322 on muscle atrophy in Dex-treated mice. Our data may provide theoretical support for the use of miR-322 as a novel therapeutic target for Dex-induced muscle atrophy
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