Myostatin-induced inhibition of the long noncoding RNA Malat1 is associated with decreased myogenesis

2013 ◽  
Vol 304 (10) ◽  
pp. C995-C1001 ◽  
Author(s):  
Rani Watts ◽  
Virginia L. Johnsen ◽  
Jane Shearer ◽  
Dustin S. Hittel
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Cell Growth ◽  
Noncoding Rna ◽  
Transforming Growth Factor ◽  
Day Treatment ◽  
Global Gene Expression ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Human Skeletal Muscle Cells

Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily of secreted proteins, is a potent negative regulator of myogenesis. Free myostatin induces the phosphorylation of the Smad family of transcription factors, which, in turn, regulates gene expression, via the canonical TGF-β signaling pathway. There is, however, emerging evidence that myostatin can regulate gene expression independent of Smad signaling. As such, we acquired global gene expression data from the gastrocnemius muscle of C57BL/6 mice following a 6-day treatment with recombinant myostatin compared with vehicle-treated animals. Of the many differentially expressed genes, the myostatin-associated decrease (−11.20-fold; P < 0.05) in the noncoding metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was the most significant and the most intriguing because of numerous reports describing its novel role in regulating cell growth. We therefore sought to further characterize the role of Malat1 expression in skeletal muscle myogenesis. RT-PCR-based quantification of C2C12 and primary human skeletal muscle cells revealed a significant and persistent upregulation (4- to 7-fold; P < 0.05) of Malat1 mRNA during the differentiation of myoblasts into myotubes. Conversely, targeted knockdown of Malat1 using siRNA suppressed myoblast proliferation by arresting cell growth in the G0/G1phase. These results reveal Malat1 as novel downstream target of myostatin with a considerable ability to regulate myogenesis. The identification of new targets of myostatin will have important repercussions for regenerative biology through inhibition and/or reversal of muscle atrophy and wasting diseases.

Myostatin: a modulator of skeletal-muscle stem cells

2005 ◽  
Vol 33 (6) ◽  
pp. 1513-1517 ◽  
Author(s):  
F.S. Walsh ◽  
A.J. Celeste
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Muscle Development ◽  
Transforming Growth Factor ◽  
Neutralizing Antibody ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Mdx Mouse ◽  
Specific Expression ◽  
Myostatin Gene

Myostatin, or GDF-8 (growth and differentiation factor-8), was first identified through sequence identity with members of the BMP (bone morphogenetic protein)/TGF-β (transforming growth factor-β) superfamily. The skeletal-muscle-specific expression pattern of myostatin suggested a role in muscle development. Mice with a targeted deletion of the myostatin gene exhibit a hypermuscular phenotype. In addition, inactivating mutations in the myostatin gene have been identified in ‘double muscled’ cattle breeds, such as the Belgian Blue and Piedmontese, as well as in a hypermuscular child. These findings define myostatin as a negative regulator of skeletal-muscle development. Myostatin binds with high affinity to the receptor serine threonine kinase ActRIIB (activin type IIB receptor), which initiates signalling through a smad2/3-dependent pathway. In an effort to validate myostatin as a therapeutic target in a post-embryonic setting, a neutralizing antibody was developed by screening for inhibition of myostatin binding to ActRIIB. Administration of this antimyostatin antibody to adult mice resulted in a significant increase in both muscle mass and functional strength. Importantly, similar results were obtained in a murine model of muscular dystrophy, the mdx mouse. Unlike the myostatin-deficient animals, which exhibit both muscle hypertrophy and hyperplasia, the antibody-treated mice demonstrate increased musculature through a hypertrophic mechanism. These results validate myostatin inhibition as a therapeutic approach to muscle wasting diseases such as muscular dystrophy, sarcopenic frailty of the elderly and amylotrophic lateral sclerosis.

Transforming growth factor β-1 enhances Smad transcriptional activity through activation of p8 gene expression

2001 ◽  
Vol 357 (1) ◽  
pp. 249-253 ◽  
Author(s):  
Andrés C. GARCÍA-MONTERO ◽  
Sophie VASSEUR ◽  
Luciana E. GIONO ◽  
Eduardo CANEPA ◽  
Silvia MORENO ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Cell Growth ◽  
Mrna Expression ◽  
Transcriptional Activity ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mouse Embryonic Fibroblasts ◽  
Expression Plasmid ◽  
Embryonic Fibroblasts

We report that exposure of mouse embryonic fibroblasts to transforming growth factor β-1 (TGFβ-1) (5ng/ml) results in a strong activation of p8 mRNA expression that precedes the induction of cell growth. Involvement of the p8 promoter in the regulation was demonstrated by using a p8–chloramphenicol acetyltransferase construct. We therefore speculated that p8 might be a mediator of TGFβ-1 in these cells. The incorporation of [3H]thymidine on treatment with TGFβ-1 was indeed significantly higher in p8+/+ fibroblasts than in p8−/− fibroblasts. Smad transcriptional activity was used as marker of the TGFβ-1 signalling pathway, to probe the lower p8−/− response to TGFβ-1. Two Smad-binding elements (SBEs)–luciferase constructs were transfected into p8−/− and p8+/+ embryonic fibroblasts before treatment with TGFβ-1. A lower level of Smad transactivation was observed in p8−/− embryonic fibroblasts, under basal conditions and after stimulation with TGFβ-1. To test whether Smad underexpression in p8−/− cells was actually due to p8 depletion, p8−/− embryonic fibroblasts were transfected with a human p8 expression plasmid together with an SBE–luciferase construct. The expression of p8 restored Smad transactivation in unstimulated and TGFβ-1-treated cells to the level found in p8+/+ cells. We concluded that TGFβ-1 activates p8 expression, which in turn enhances the Smad-transactivating function responsible for TGFβ-1 activity.

Chronic hypoxia attenuates resting and exercise-induced VEGF, flt-1, and flk-1 mRNA levels in skeletal muscle

2001 ◽  
Vol 90 (4) ◽  
pp. 1532-1538 ◽  
Author(s):  
I. Mark Olfert ◽  
Ellen C. Breen ◽  
Odile Mathieu-Costello ◽  
Peter D. Wagner
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Chronic Hypoxia ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mammalian Skeletal Muscle ◽  
Fibroblast Growth

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic mitogen. However, chronic hypoxia is generally not found to increase mammalian skeletal muscle capillarity. We sought to determine the effect of chronic hypoxia (8 wk, inspired O2 fraction = 0.12) on skeletal muscle gene expression of VEGF, its receptors (flt-1 and flk-1), basic fibroblast growth factor, and transforming growth factor-β1. Wistar rats were exposed to chronic hypoxia ( n = 12) or room air ( n = 12). After the exposure period, six animals from each group were subjected to a single 1-h treadmill exercise bout (18 m/min on a 10° incline) in room air while the remaining six animals served as rest controls. Morphological analysis revealed that chronic hypoxia did not increase skeletal muscle capillarity. Northern blot analyses showed that chronic hypoxia decreased resting VEGF, flt-1, and flk-1 mRNA by 23, 68, and 42%, respectively ( P < 0.05). The VEGF mRNA response to exercise was also decreased (4.1- and 2.7-fold increase in room air and chronic hypoxia, respectively, P < 0.05). In contrast, neither transforming growth factor-β1 nor basic fibroblast growth factor mRNA was significantly altered by chronic hypoxia. In conclusion, prolonged exposure to hypoxia attenuated gene expression of VEGF and its receptors flt-1 and flk-1 in rat gastrocnemius muscle. These findings may provide an explanation for the lack of mammalian skeletal muscle angiogenesis that is observed after chronic hypoxia.

scholarly journals Enhanced Intestinal TGF-β/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 806
Author(s):  
Nongthombam Boby ◽  
Alyssa Ransom ◽  
Barcley T. Pace ◽  
Kelsey M. Williams ◽  
Christopher Mabee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Simian Immunodeficiency Virus ◽  
Transforming Growth Factor ◽  
Rhesus Macaques ◽  
Transforming Growth Factor Β ◽  
Immunodeficiency Virus ◽  
Cellular Source ◽  
Siv Infection ◽  
Β Receptor ◽  
Differentiation And Proliferation

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-β in a majority of intestinal CD3−CD20−CD68+ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4+ T cells. No significant changes in intestinal TGF-β receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-β production by intestinal CD3−CD20−CD68+ cells and increased TGF-β/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-β and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-β production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-β expression by therapeutic TGF-β blockers may help to create effective antiviral mucosal immune responses.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

scholarly journals Transforming growth factor β-1 enhances Smad transcriptional activity through activation of p8 gene expression

2001 ◽  
Vol 357 (1) ◽  
pp. 249 ◽  
Author(s):  
Andrés C. GARCÍA-MONTERO ◽  
Sophie VASSEUR ◽  
Luciana E. GIONO ◽  
Eduardo CANEPA ◽  
Silvia MORENO ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Transcriptional Activity ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β

Long Noncoding RNA MIAT Modulates the Extracellular Matrix Deposition in Leiomyomas by Sponging MiR-29 Family

Endocrinology ◽  
2021 ◽  
Vol 162 (11) ◽  
Author(s):  
Tsai-Der Chuang ◽  
Derek Quintanilla ◽  
Drake Boos ◽  
Omid Khorram
Keyword(s):  
Extracellular Matrix ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Luciferase Reporter ◽  
Cycle Phase ◽  
Type I ◽  
Matrix Deposition

Abstract The objective of this study was to determine the expression and functional role of a long noncoding RNA (lncRNA) MIAT (myocardial infarction–associated transcript) in leiomyoma pathogenesis. Leiomyoma compared with myometrium (n = 66) expressed significantly more MIAT that was independent of race/ethnicity and menstrual cycle phase but dependent on MED12 (mediator complex subunit 12) mutation status. Leiomyomas bearing the MED12 mutation expressed higher levels of MIAT and lower levels of microRNA 29 family (miR-29a, -b, and -c) compared with MED12 wild-type leiomyomas. Using luciferase reporter activity and RNA immunoprecipitation analysis, MIAT was shown to sponge the miR-29 family. In a 3-dimensional spheroid culture system, transient transfection of MIAT siRNA in leiomyoma smooth muscle cell (LSMC) spheroids resulted in upregulation of miR-29 family and downregulation of miR-29 targets, collagen type I (COL1A1), collagen type III (COL3A1), and TGF-β3 (transforming growth factor β-3). Treatment of LSMC spheroids with TGF-β3 induced COL1A1, COL3A1, and MIAT levels, but repressed miR-29 family expression. Knockdown of MIAT in LSMC spheroids blocked the effects of TGF-β3 on the induction of COL1A1 and COL3A1 expression. Collectively, these results underscore the physiological significance of MIAT in extracellular matrix accumulation in leiomyoma.

Sign in / Sign up

Export Citation Format

Share Document