Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression

2003 ◽  
Vol 285 (2) ◽  
pp. E363-E371 ◽  
Author(s):  
Kun Ma ◽  
Con Mallidis ◽  
Shalender Bhasin ◽  
Vahid Mahabadi ◽  
Jorge Artaza ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Muscle Atrophy ◽  
Muscular Atrophy ◽  
Day Treatment ◽  
Negative Regulator ◽  
Skeletal Muscle Atrophy ◽  
Muscle Loss ◽  
Myostatin Gene ◽  
Dose Dependent

The mechanisms by which excessive glucocorticoids cause muscular atrophy remain unclear. We previously demonstrated that dexamethasone increases the expression of myostatin, a negative regulator of skeletal muscle mass, in vitro. In the present study, we tested the hypothesis that dexamethasone-induced muscle loss is associated with increased myostatin expression in vivo. Daily administration (60, 600, 1,200 μg/kg body wt) of dexamethasone for 5 days resulted in rapid, dose-dependent loss of body weight (-4.0, -13.4, -17.2%, respectively, P < 0.05 for each comparison), and muscle atrophy (6.3, 15.0, 16.6% below controls, respectively). These changes were associated with dose-dependent, marked induction of intramuscular myostatin mRNA (66.3, 450, 527.6% increase above controls, P < 0.05 for each comparison) and protein expression (0.0, 260.5, 318.4% increase above controls, P < 0.05). We found that the effect of dexamethasone on body weight and muscle loss and upregulation of intramuscular myostatin expression was time dependent. When dexamethasone treatment (600 μg · kg-1 · day-1) was extended from 5 to 10 days, the rate of body weight loss was markedly reduced to ∼2% within this extended period. The concentrations of intramuscular myosin heavy chain type II in dexamethasone-treated rats were significantly lower (-43% after 5-day treatment, -14% after 10-day treatment) than their respective corresponding controls. The intramuscular myostatin concentration in rats treated with dexamethasone for 10 days returned to basal level. Concurrent treatment with RU-486 blocked dexamethasone-induced myostatin expression and significantly attenuated body loss and muscle atrophy. We propose that dexamethasone-induced muscle loss is mediated, at least in part, by the upregulation of myostatin expression through a glucocorticoid receptor-mediated pathway.

scholarly journals Expression Levels of Long Non-Coding RNAs Change in Models of Altered Muscle Activity and Muscle Mass

2020 ◽  
Vol 21 (5) ◽  
pp. 1628 ◽  
Author(s):  
Keisuke Hitachi ◽  
Masashi Nakatani ◽  
Shiori Funasaki ◽  
Ikumi Hijikata ◽  
Mizuki Maekawa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Skeletal Muscle Mass ◽  
Muscle Size ◽  
Skeletal Muscle Atrophy ◽  
Myostatin Gene ◽  
Expression Levels ◽  
Non Coding Rnas

Skeletal muscle is a highly plastic organ that is necessary for homeostasis and health of the human body. The size of skeletal muscle changes in response to intrinsic and extrinsic stimuli. Although protein-coding RNAs including myostatin, NF-κβ, and insulin-like growth factor-1 (IGF-1), have pivotal roles in determining the skeletal muscle mass, the role of long non-coding RNAs (lncRNAs) in the regulation of skeletal muscle mass remains to be elucidated. Here, we performed expression profiling of nine skeletal muscle differentiation-related lncRNAs (DRR, DUM1, linc-MD1, linc-YY1, LncMyod, Neat1, Myoparr, Malat1, and SRA) and three genomic imprinting-related lncRNAs (Gtl2, H19, and IG-DMR) in mouse skeletal muscle. The expression levels of these lncRNAs were examined by quantitative RT-PCR in six skeletal muscle atrophy models (denervation, casting, tail suspension, dexamethasone-administration, cancer cachexia, and fasting) and two skeletal muscle hypertrophy models (mechanical overload and deficiency of the myostatin gene). Cluster analyses of these lncRNA expression levels were successfully used to categorize the muscle atrophy models into two sub-groups. In addition, the expression of Gtl2, IG-DMR, and DUM1 was altered along with changes in the skeletal muscle size. The overview of the expression levels of lncRNAs in multiple muscle atrophy and hypertrophy models provides a novel insight into the role of lncRNAs in determining the skeletal muscle mass.

Dynamics of Toll-like receptors signaling in skeletal muscle atrophy

2021 ◽  
Vol 28 ◽  
Author(s):  
Aarti Yadav ◽  
Anil Dahuja ◽  
Rajesh Dabur
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Inflammatory Cytokine ◽  
Muscle Growth ◽  
Skeletal Muscle Atrophy ◽  
Muscle Loss ◽  
Protein Catabolism ◽  
Tlr Signaling ◽  
Recent Advancement ◽  
And Oxidative Stress

: Skeletal muscle atrophy has been characterizedas a state of uncontrolled inflammation and oxidative stress that escalates the protein catabolism. Recent advancement supportsthat impinging signaling molecules in the muscle fibers controlled throughtoll-like receptors (TLR). Activated TLR signalingpathways have been identified as inhibitors of muscle mass and provoke the settings for muscle atrophy. Among them, mainly TLR2 and TLR4 manifest their presence to exacerbate the release of the pro-inflammatory cytokine to deform the synchronized muscle programming. The present review enlightens the TLR signaling mediated muscle loss and their interplay betweeninflammationand skeletal muscle growth.

MERG1A Protein Abundance Increases in the Atrophied Skeletal Muscle of Denervated Mice, But Does Not Affect NFκB Activity

2021 ◽  
Author(s):  
Luke B Anderson ◽  
Barbara Ravara ◽  
Sohaib Hameed ◽  
Chase D Latour ◽  
Sawyer M Latour ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Gastrocnemius Muscle ◽  
Ectopic Expression ◽  
Dominant Negative ◽  
Skeletal Muscle Atrophy ◽  
K Channel ◽  
Protein Abundance ◽  
Muscle Loss ◽  
Ubiquitin Proteasome

Abstract Skeletal muscle atrophy may occur with disease, injury, decreased muscle use, starvation, and normal aging. No reliably effective treatments for atrophy are available, thus research into the mechanisms contributing to muscle loss is essential. The ERG1A K+ channel contributes to muscle loss by increasing ubiquitin proteasome proteolysis (UPP) in the skeletal muscle of both unweighted and cachectic mice. Because the mechanisms which produce atrophy vary based upon the initiating factor, here we investigate atrophy produced by denervation. Using immunohistochemistry and immunoblots, we demonstrate that ERG1A protein abundance increases significantly in the Gastrocnemius muscle of rodents 7 days after both sciatic nerve transection and hind limb unweighting. Further, we reveal that ectopic expression of a Merg1a encoded plasmid in normal mouse Gastrocnemius muscle has no effect on activity of the NFκB transcription factor family, a group of proteins which contribute to muscle atrophy by modulation of the UPP. Further, although NFκB activity increases significantly after denervation, we show that expression of a plasmid encoding a dominant negative Merg1a mutant in Gastrocnemius muscle prior to denervation, has no effect on NFκB activity. Thus, although the ERG1A K+ channel increases UPP, it does not do so through modulation of NFκB transcription factors.

Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size

2009 ◽  
Vol 296 (6) ◽  
pp. C1258-C1270 ◽  
Author(s):  
Anne Ulrike Trendelenburg ◽  
Angelika Meyer ◽  
Daisy Rohner ◽  
Joseph Boyle ◽  
Shinji Hatakeyama ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Transforming Growth Factor ◽  
Negative Regulator ◽  
Bone Morphogenetic Protein 2 ◽  
Muscle Size ◽  
Skeletal Muscle Atrophy ◽  
Myoblast Differentiation ◽  
Activin Receptor

Myostatin is a negative regulator of skeletal muscle size, previously shown to inhibit muscle cell differentiation. Myostatin requires both Smad2 and Smad3 downstream of the activin receptor II (ActRII)/activin receptor-like kinase (ALK) receptor complex. Other transforming growth factor-β (TGF-β)-like molecules can also block differentiation, including TGF-β1, growth differentiation factor 11 (GDF-11), activins, bone morphogenetic protein 2 (BMP-2) and BMP-7. Myostatin inhibits activation of the Akt/mammalian target of rapamycin (mTOR)/p70S6 protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes. Blockade of the Akt/mTOR pathway, using small interfering RNA to regulatory-associated protein of mTOR (RAPTOR), a component of TOR signaling complex 1 (TORC1), increases myostatin-induced phosphorylation of Smad2, establishing a myostatin signaling-amplification role for blockade of Akt. Blockade of RAPTOR also facilitates myostatin's inhibition of muscle differentiation. Inhibition of TORC2, via rapamycin-insensitive companion of mTOR (RICTOR), is sufficient to inhibit differentiation on its own. Furthermore, myostatin decreases the diameter of postdifferentiated myotubes. However, rather than causing upregulation of the E3 ubiquitin ligases muscle RING-finger 1 ( MuRF1) and muscle atrophy F-box ( MAFbx), previously shown to mediate skeletal muscle atrophy, myostatin decreases expression of these atrophy markers in differentiated myotubes, as well as other genes normally upregulated during differentiation. These findings demonstrate that myostatin signaling acts by blocking genes induced during differentiation, even in a myotube, as opposed to activating the distinct “atrophy program.” In vivo, inhibition of myostatin increases muscle creatine kinase activity, coincident with an increase in muscle size, demonstrating that this in vitro differentiation measure is also upregulated in vivo.

scholarly journals Overexpression of NF90-NF45 Represses Myogenic MicroRNA Biogenesis, Resulting in Development of Skeletal Muscle Atrophy and Centronuclear Muscle Fibers

2015 ◽  
Vol 35 (13) ◽  
pp. 2295-2308 ◽  
Author(s):  
Hiroshi Todaka ◽  
Takuma Higuchi ◽  
Ken-ichi Yagyu ◽  
Yasunori Sugiyama ◽  
Fumika Yamaguchi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Fibers ◽  
Negative Regulator ◽  
Skeletal Muscle Atrophy ◽  
Mirna Biogenesis ◽  
Centronuclear Myopathy ◽  
Causative Gene ◽  
Dynamin 2

MicroRNAs (miRNAs) are involved in the progression and suppression of various diseases through translational inhibition of target mRNAs. Therefore, the alteration of miRNA biogenesis induces several diseases. The nuclear factor 90 (NF90)-NF45 complex is known as a negative regulator in miRNA biogenesis. Here, we showed that NF90-NF45 double-transgenic (dbTg) mice develop skeletal muscle atrophy and centronuclear muscle fibers in adulthood. Subsequently, we found that the levels of myogenic miRNAs, including miRNA 133a (miR-133a), which promote muscle maturation, were significantly decreased in the skeletal muscle of NF90-NF45 dbTg mice compared with those in wild-type mice. However, levels of primary transcripts of the miRNAs (pri-miRNAs) were clearly elevated in NF90-NF45 dbTg mice. This result indicated that the NF90-NF45 complex suppressed miRNA production through inhibition of pri-miRNA processing. This finding was supported by the fact that processing of pri-miRNA 133a-1 (pri-miR-133a-1) was inhibited via binding of NF90-NF45 to the pri-miRNA. Finally, the level of dynamin 2, a causative gene of centronuclear myopathy and concomitantly a target of miR-133a, was elevated in the skeletal muscle of NF90-NF45 dbTg mice. Taken together, we conclude that the NF90-NF45 complex induces centronuclear myopathy through increased dynamin 2 expression by an NF90-NF45-induced reduction of miR-133a expressionin vivo.

scholarly journals HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation

2021 ◽  
Vol 15 ◽  
Author(s):  
Wenjing Ma ◽  
Yong Cai ◽  
Yuntian Shen ◽  
Xin Chen ◽  
Lilei Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscular Atrophy ◽  
Underlying Mechanism ◽  
Skeletal Muscle Atrophy ◽  
Regulation Mechanism ◽  
Type I ◽  
Muscle Adaptation ◽  
Cross Sectional

Denervation can activate the catabolic pathway in skeletal muscle and lead to progressive skeletal muscle atrophy. At present, there is no effective treatment for muscle atrophy. Histone deacetylase 4 (HDAC4) has recently been found to be closely related to muscle atrophy, but the underlying mechanism of HDAC4 in denervation-induced muscle atrophy have not been described clearly yet. In this study, we found that the expression of HDAC4 increased significantly in denervated skeletal muscle. HDAC4 inhibition can effectively diminish denervation-induced muscle atrophy, reduce the expression of muscle specific E3 ubiquitin ligase (MuRF1 and MAFbx) and autophagy related proteins (Atg7, LC3B, PINK1 and BNIP3), inhibit the transformation of type I fibers to type II fibers, and enhance the expression of SIRT1 and PGC-1 α. Transcriptome sequencing and bioinformatics analysis was performed and suggested that HDAC4 may be involved in denervation-induced muscle atrophy by regulating the response to denervation involved in the regulation of muscle adaptation, cell division, cell cycle, apoptotic process, skeletal muscle atrophy, and cell differentiation. STRING analysis showed that HDAC4 may be involved in the process of muscle atrophy by directly regulating myogenin (MYOG), cell cycle inhibitor p21 (CDKN1A) and salt induced kinase 1 (SIK1). MYOG was significantly increased in denervated skeletal muscle, and MYOG inhibition could significantly alleviate denervation-induced muscle atrophy, accompanied by the decreased MuRF1 and MAFbx. MYOG overexpression could reduce the protective effect of HDAC4 inhibition on denervation-induced muscle atrophy, as evidenced by the decreased muscle mass and cross-sectional area of muscle fibers, and the increased mitophagy. Taken together, HDAC4 inhibition can alleviate denervation-induced muscle atrophy by reducing MYOG expression, and HDAC4 is also directly related to CDKN1A and SIK1 in skeletal muscle, which suggests that HDAC4 inhibitors may be a potential drug for the treatment of neurogenic muscle atrophy. These results not only enrich the molecular regulation mechanism of denervation-induced muscle atrophy, but also provide the experimental basis for HDAC4-MYOG axis as a new target for the prevention and treatment of muscular atrophy.

scholarly journals Supplementary Oral Anamorelin Mitigates Anorexia and Skeletal Muscle Atrophy Induced by Gemcitabine Plus Cisplatin Systemic Chemotherapy in a Mouse Model

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1942 ◽  
Author(s):  
Makito Miyake ◽  
Shunta Hori ◽  
Yoshitaka Itami ◽  
Yuki Oda ◽  
Takuya Owari ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Food Intake ◽  
Adverse Effects ◽  
Mouse Model ◽  
Muscle Atrophy ◽  
Combination Chemotherapy ◽  
Aminolevulinic Acid ◽  
Skeletal Muscle Atrophy ◽  
Gemcitabine And Cisplatin

Chemotherapy-induced adverse effects can reduce the relative dose intensity and quality of life. In this study, we investigated the potential benefit of supplementary anamorelin and 5-aminolevulinic acid (5-ALA) as preventive interventions against a gemcitabine and cisplatin (GC) combination chemotherapy-induced adverse effects in a mouse model. Non-cancer-bearing C3H mice were randomly allocated as follows and treated for 2 weeks—(1) non-treated control, (2) oral anamorelin alone, (3) oral 5-ALA alone, (4) gemcitabine and cisplatin (GC) chemotherapy, (5) GC plus anamorelin, and (6) GC plus 5-ALA. GC chemotherapy significantly decreased body weight, food intake, skeletal muscle mass and induced severe gastric mucositis, which resulted in decreased ghrelin production and blood ghrelin level. The supplementation of oral anamorelin to GC chemotherapy successfully mitigated decrease of food intake during the treatment period and body weight loss at day 8. In addition, analysis of the resected muscles and stomach revealed that anamorelin suppressed chemotherapy-induced skeletal muscle atrophy by mediating the downregulation of forkhead box protein O-1 (FOXO1)/atrogin-1 signaling and gastric damage. Our findings suggest the preventive effect of anamorelin against GC combination chemotherapy, which was selected for patients with some types of advanced malignancies in clinical practice.

The estrous cycle and skeletal muscle atrophy: Investigations in rodent models of muscle loss

2021 ◽  
Author(s):  
Megan E. Rosa‐Caldwell ◽  
Marie Mortreux ◽  
Ursula B. Kaiser ◽  
Dong‐Min Sung ◽  
Mary L. Bouxsein ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Estrous Cycle ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Rodent Models ◽  
Muscle Loss

scholarly journals Skeletal muscle proteolysis in response to short-term unloading in humans

2008 ◽  
Vol 105 (3) ◽  
pp. 902-906 ◽  
Author(s):  
Per A. Tesch ◽  
Ferdinand von Walden ◽  
Thomas Gustafsson ◽  
Richard M. Linnehan ◽  
Todd A. Trappe
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Simulated Microgravity ◽  
Skeletal Muscle Atrophy ◽  
Muscle Loss ◽  
Short Term ◽  
Promising Tool ◽  
Muscle Disuse ◽  
Naturally Occurring ◽  
Muscle Contractile

Skeletal muscle atrophy is evident after muscle disuse, unloading, or spaceflight and results from decreased protein content as a consequence of decreased protein synthesis, increased protein breakdown or both. At this time, there are essentially no human data describing proteolysis in skeletal muscle undergoing atrophy on Earth or in space, primarily due to lack of valid and accurate methodology. This particular study aimed at assessing the effects of short-term unloading on the muscle contractile proteolysis rate. Eight men were subjected to 72-h unilateral lower limb suspension (ULLS) and intramuscular interstitial levels of the naturally occurring proteolytic tracer 3-methylhistidine (3MH) were measured by means of microdialysis before and on completion of this intervention. The 3MH concentration following 72-h ULLS (2.01 ± 0.22 nmol/ml) was 44% higher ( P < 0.05) than before ULLS (1.56 ± 0.20 nmol/ml). The present experimental model and the employed method determining 3MH in microdialysates present a promising tool for monitoring skeletal muscle proteolysis or metabolism of specific muscles during conditions resulting in atrophy caused by, e.g., disuse and real or simulated microgravity. This study provides evidence that the atrophic processes are evoked rapidly and within 72 h of unloading and suggests that countermeasures should be employed in the early stages of space missions to offset or prevent muscle loss during the period when the rate of muscle atrophy is the highest.

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.

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