scholarly journals Identification of potential target genes associated with the reversion of androgen-dependent skeletal muscle atrophy

2019 ◽  
Vol 663 ◽  
pp. 173-182 ◽  
Author(s):  
Priscila de O. Coelho ◽  
Flavia A. Guarnier ◽  
Leonardo Bruno Figueiredo ◽  
Livia S. Zaramela ◽  
Enio S.A. Pacini ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Target Genes ◽  
Skeletal Muscle Atrophy ◽  
Potential Target

scholarly journals MicroRNA 322 Aggravates Dexamethasone-Induced Muscle Atrophy by Targeting IGF1R and INSR

2020 ◽  
Vol 21 (3) ◽  
pp. 1111 ◽  
Author(s):  
Hongwei Geng ◽  
Qinglong Song ◽  
Yunyun Cheng ◽  
Haoyang Li ◽  
Rui Yang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Target Genes ◽  
Immunosuppressive Agent ◽  
Skeletal Muscle Atrophy ◽  
Luciferase Reporter ◽  
C2c12 Myotubes ◽  
High Dose ◽  
Reporter Assays ◽  
Underlying Mechanisms

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.

scholarly journals Metronidazole Causes Skeletal Muscle Atrophy and Modulates Muscle Chronometabolism

2018 ◽  
Vol 19 (8) ◽  
pp. 2418 ◽  
Author(s):  
Ravikumar Manickam ◽  
Hui Oh ◽  
Chek Tan ◽  
Eeswari Paramalingam ◽  
Walter Wahli
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Metabolic Regulation ◽  
Target Genes ◽  
Clock Genes ◽  
Tibialis Anterior Muscle ◽  
Skeletal Muscle Atrophy ◽  
Muscle Weight ◽  
Expression Of Genes ◽  
Specific Pathogen

Antibiotics lead to increased susceptibility to colonization by pathogenic organisms, with different effects on the host-microbiota relationship. Here, we show that metronidazole treatment of specific pathogen-free (SPF) mice results in a significant increase of the bacterial phylum Proteobacteria in fecal pellets. Furthermore, metronidazole in SPF mice decreases hind limb muscle weight and results in smaller fibers in the tibialis anterior muscle. In the gastrocnemius muscle, metronidazole causes upregulation of Hdac4, myogenin, MuRF1, and atrogin1, which are implicated in skeletal muscle neurogenic atrophy. Metronidazole in SPF mice also upregulates skeletal muscle FoxO3, described as involved in apoptosis and muscle regeneration. Of note, alteration of the gut microbiota results in increased expression of the muscle core clock and effector genes Cry2, Ror-β, and E4BP4. PPARγ and one of its important target genes, adiponectin, are also upregulated by metronidazole. Metronidazole in germ-free (GF) mice increases the expression of other core clock genes, such as Bmal1 and Per2, as well as the metabolic regulators FoxO1 and Pdk4, suggesting a microbiota-independent pharmacologic effect. In conclusion, metronidazole in SPF mice results in skeletal muscle atrophy and changes the expression of genes involved in the muscle peripheral circadian rhythm machinery and metabolic regulation.

scholarly journals A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure

2012 ◽  
Vol 302 (10) ◽  
pp. E1210-E1220 ◽  
Author(s):  
Monica L. Watson ◽  
Leslie M. Baehr ◽  
Holger M. Reichardt ◽  
Jan P. Tuckermann ◽  
Sue C. Bodine ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucocorticoid Receptor ◽  
Muscle Atrophy ◽  
Target Genes ◽  
Prolonged Exposure ◽  
Skeletal Muscle Atrophy ◽  
High Dose ◽  
Nerve Lesion ◽  
Nutritional Deprivation

Glucocorticoids (GCs) are important regulators of skeletal muscle mass, and prolonged exposure will induce significant muscle atrophy. To better understand the mechanism of skeletal muscle atrophy induced by elevated GC levels, we examined three different models: exogenous synthetic GC treatment [dexamethasone (DEX)], nutritional deprivation, and denervation. Specifically, we tested the direct contribution of the glucocorticoid receptor (GR) in skeletal muscle atrophy by creating a muscle-specific GR-knockout mouse line (MGRe3KO) using Cre-lox technology. In MGRe3KO mice, we found that the GR is essential for muscle atrophy in response to high-dose DEX treatment. In addition, DEX regulation of multiple genes, including two important atrophy markers, MuRF1 and MAFbx, is eliminated completely in the MGRe3KO mice. In a condition where endogenous GCs are elevated, such as nutritional deprivation, induction of MuRF1 and MAFbx was inhibited, but not completely blocked, in MGRe3KO mice. In response to sciatic nerve lesion and hindlimb muscle denervation, muscle atrophy and upregulation of MuRF1 and MAFbx occurred to the same extent in both wild-type and MGRe3KO mice, indicating that a functional GR is not required to induce atrophy under these conditions. Therefore, we demonstrate conclusively that the GR is an important mediator of skeletal muscle atrophy and associated gene expression in response to exogenous synthetic GCs in vivo and that the MGRe3KO mouse is a useful model for studying the role of the GR and its target genes in multiple skeletal muscle atrophy models.

scholarly journals Identification of Potential miRNA-mRNA Regulatory Network in Denervated Muscular Atrophy by Bioinformatics Analysis

2021 ◽  
Author(s):  
Jianhua Wang ◽  
Yuhang Liu ◽  
Yongming Zhang ◽  
Bin Liu ◽  
Zhijian Wei
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Regulatory Network ◽  
Target Genes ◽  
Muscular Atrophy ◽  
Enrichment Analysis ◽  
Skeletal Muscle Atrophy ◽  
Pathway Enrichment Analysis ◽  
Denervated Muscle ◽  
Hub Genes

Abstract Background Muscle atrophy caused by long-term denervation leads to the loss of skeletal muscle mass and strength, resulting in a poor recovery of functional muscles and decreasing quality of life. Increasing differentially expressed microRNAs (DEMs) have been reported to be involved in the pathogenesis of denervated muscle atrophy. However, there is still insufficient evidence to explain the role of miRNAs and their target genes in skeletal muscle atrophy. Therefore, an integrative exploration of the miRNA-mRNA regulatory network in denervated muscle atrophy is necessary. Results A total of 21 (16 upregulated and 5 downregulated) DEMs were screened out in the GSE81914 dataset. Med1 was predicted and verified to be significantly upregulated, which may affect the process of denervated muscle atrophy by regulating mir-146b and mir-1949. 59 target genes were then predicted by submitting candidate DEMs to the miRNet database. GO and KEGG pathway enrichment analysis showed that target genes of DEMs were mainly enriched in the apoptotic process and PI3K/Akt signaling pathway. Through the PPI network construction, key modules and hub genes were obtained and potentially modulated by mir-29b, mir-132, and mir-133a. According to the qRT-PCR results, among the hub genes, Ctgf was significantly increased, which was consistent with the decreased mir-133a in denervated muscle atrophy. Conclusions In the study, a potential miRNA-mRNA regulatory network was firstly constructed in denervated muscle atrophy. Two potential miRNA–mRNA pathways (miR-29b-COL1A1 and mir-133a-Ctgf) may provide new insight into the pathogenesis and treatment of denervated muscle atrophy.

Role for IκBα, but not c-Rel, in skeletal muscle atrophy

2007 ◽  
Vol 292 (1) ◽  
pp. C372-C382 ◽  
Author(s):  
Andrew R. Judge ◽  
Alan Koncarevic ◽  
R. Bridge Hunter ◽  
Hsiou-Chi Liou ◽  
Robert W. Jackman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Target Genes ◽  
Weight Bearing ◽  
Family Members ◽  
Dominant Negative ◽  
Hindlimb Unloading ◽  
Skeletal Muscle Atrophy ◽  
Significant Advance ◽  
Protein Ubiquitination

Skeletal muscle atrophy is associated with a marked and sustained activation of nuclear factor-κB (NF-κB) activity. Previous work showed that p50 is one of the NF-κB family members required for this activation and for muscle atrophy. In this work, we tested whether another NF-κB family member, c-Rel, is required for atrophy. Because endogenous inhibitory factor κBα (IκBα) was activated (i.e., decreased) at 3 and 7 days of muscle disuse (i.e., hindlimb unloading), we also tested if IκBα, which binds and retains Rel proteins in the cytosol, is required for atrophy and intermediates of the atrophy process. To do this, we electrotransferred a dominant negative IκBα (IκBαΔN) in soleus muscles, which were either unloaded or weight bearing. IκBαΔN expression abolished the unloading-induced increase in both NF-κB activation and total ubiquitinated protein. IκBαΔN inhibited unloading-induced fiber atrophy by 40%. The expression of certain genes known to be upregulated with atrophy were significantly inhibited by IκBαΔN expression during unloading, including MAFbx/atrogin-1, Nedd4, IEX, 4E-BP1, FOXO3a, and cathepsin L, suggesting these genes may be targets of NF-κB transcription factors. In contrast, c-Rel was not required for atrophy because the unloading-induced markers of atrophy were the same in c-rel−/− and wild-type mice. Thus IκBα degradation is required for the unloading-induced decrease in fiber size, the increase in protein ubiquitination, activation of NF-κB signaling, and the expression of specific atrophy genes, but c-Rel is not. These data represent a significant advance in our understanding of the role of NF-κB/IκB family members in skeletal muscle atrophy, and they provide new candidate NF-κB target genes for further study.

scholarly journals Identification of Potential miRNA-mRNA Regulatory Network in Denervated Muscular Atrophy by Bioinformatics Analysis

2021 ◽  
Author(s):  
Jianhua Wang ◽  
Yuhang Liu ◽  
Yongming Zhang ◽  
Bin Liu ◽  
Zhijian Wei
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Regulatory Network ◽  
Target Genes ◽  
Muscular Atrophy ◽  
Enrichment Analysis ◽  
Skeletal Muscle Atrophy ◽  
Pathway Enrichment Analysis ◽  
Denervated Muscle ◽  
Hub Genes

Abstract Muscle atrophy caused by long-term denervation leads to the loss of skeletal muscle mass and strength, resulting in a poor recovery of functional muscles and decreasing quality of life. Increasing differentially expressed microRNAs (DEMs) have been reported to be involved in the pathogenesis of denervated muscle atrophy. However, there is still insufficient evidence to explain the role of miRNAs and their target genes in skeletal muscle atrophy. Therefore, an integrative exploration of the miRNA-mRNA regulatory network in denervated muscle atrophy is necessary. A total of 21 (16 upregulated and 5 downregulated) DEMs were screened out in the GSE81914 dataset. Med1 was predicted and verified to be significantly upregulated, which may affect the process of denervated muscle atrophy by regulating mir-146b and mir-1949. 59 target genes were then predicted by submitting candidate DEMs to the miRNet database. GO and KEGG pathway enrichment analysis showed that target genes of DEMs were mainly enriched in the apoptotic process and PI3K/Akt signaling pathway. Through the PPI network construction, key modules and hub genes were obtained and potentially modulated by mir-29b, mir-132, and mir-133a. According to the qRT-PCR results, among the hub genes, Ctgf was significantly increased, which was consistent with the decreased mir-133a in denervated muscle atrophy. In the study, a potential miRNA-mRNA regulatory network was firstly constructed in denervated muscle atrophy. Two potential miRNA–mRNA pathways (miR-29b-COL1A1 and mir-133a-Ctgf) may provide new insight into the pathogenesis and treatment of denervated muscle atrophy.

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