Angiotensin-(1-7) Prevents Skeletal Muscle Atrophy Induced by Transforming Growth Factor Type Beta (TGF-β) via Mas Receptor Activation

Background: Transforming growth factor type beta 1 (TGF-β1) produces skeletal muscle atrophy. Angiotensin-(1-7) (Ang-(1-7)), through the Mas receptor, prevents the skeletal muscle atrophy induced by sepsis, immobilization, or angiotensin II (Ang-II). However, the effect of Ang-(1-7) on muscle wasting induced by TGF-β1 is unknown. Aim: To evaluate whether Ang-(1-7)/Mas receptor axis could prevent the skeletal muscle atrophy induced by TGF-β1. Methods: This study assessed the atrophic effect of TGF-β1 in C2C12 myotubes and mice in absence or presence of Ang-(1-7), and the receptor participation using A779, an antagonist of the Mas receptor. The levels of myosin heavy chain (MHC), polyubiquitination, and MuRF-1 were detected by western blot. Myotube diameter was also evaluated. In vivo analysis included the muscle strength, fibre diameter, MHC and MuRF-1 levels by western blot, and ROS levels by DCF probe detection. Results: The results showed that Ang-(1-7) prevented the increase in MuRF-1 and polyubiquitined protein levels, the decrease of MHC levels, the myotubes/fibre diameter diminution, and the increased production of reactive oxygen species (ROS) induced by TGF-β1. Utilizing A779 inhibited the anti-atrophic effect of Ang-(1-7). Conclusion: The preventive effect of Ang-(1-7) on skeletal muscle atrophy induced by TGF-β1 is produced through inhibition of ROS production and proteasomal degradation of MHC.

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Transforming growth factor type beta (TGF-β) requires reactive oxygen species to induce skeletal muscle atrophy

Cellular Signalling ◽

10.1016/j.cellsig.2016.01.010 ◽

2016 ◽

Vol 28 (5) ◽

pp. 366-376 ◽

Cited By ~ 30

Author(s):

Johanna Abrigo ◽

Juan Carlos Rivera ◽

Felipe Simon ◽

Daniel Cabrera ◽

Claudio Cabello-Verrugio

Keyword(s):

Reactive Oxygen Species ◽

Skeletal Muscle ◽

Growth Factor ◽

Muscle Atrophy ◽

Transforming Growth Factor ◽

Reactive Oxygen ◽

Skeletal Muscle Atrophy ◽

Oxygen Species ◽

Factor Type

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Transforming growth factor-beta induces skeletal muscle atrophy and fibrosis through the induction of atrogin-1 and scleraxis

Muscle & Nerve ◽

10.1002/mus.22232 ◽

2011 ◽

Vol 45 (1) ◽

pp. 55-59 ◽

Cited By ~ 99

Author(s):

Christopher L. Mendias ◽

Jonathan P. Gumucio ◽

Max E. Davis ◽

Caleb W. Bromley ◽

Carol S. Davis ◽

...

Keyword(s):

Skeletal Muscle ◽

Growth Factor ◽

Muscle Atrophy ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Skeletal Muscle Atrophy ◽

Growth Factor Beta

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TGF-β requires the activation of canonical and non-canonical signalling pathways to induce skeletal muscle atrophy

Biological Chemistry ◽

10.1515/hsz-2017-0217 ◽

2018 ◽

Vol 399 (3) ◽

pp. 253-264 ◽

Cited By ~ 13

Author(s):

Johanna Ábrigo ◽

Fabian Campos ◽

Felipe Simon ◽

Claudia Riedel ◽

Daniel Cabrera ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Transforming Growth Factor ◽

Skeletal Muscle Atrophy ◽

Signalling Pathways ◽

Oxygen Species ◽

Mapk Signalling ◽

Canonical Pathways ◽

Factor Type ◽

The Impact

AbstractThe transforming growth factor type-beta (TGF-β) induces skeletal muscle atrophy characterised by a decrease in the fibre’s diameter and levels of myosin heavy chain (MHC), also as an increase of MuRF-1 expression. In addition, TGF-β induces muscle atrophy by a mechanism dependent on reactive oxygen species (ROS). TGF-β signals by activating both canonical Smad-dependent, and non-canonical signalling pathways such as ERK1/2, JNK1/2, and p38 MAPKs. However, the participation of canonical and non-canonical signalling pathways in the TGF-β atrophic effect on skeletal muscle is unknown. We evaluate the impact of Smad and MAPK signalling pathways on the TGF-β-induced atrophic effect in C2C12myotubes. The results indicate that TGF-β activates Smad2/3, ERK1/2 and JNK1/2, but not p38 in myotubes. The pharmacological inhibition of Smad3, ERK1/2 and JNK1/2 activation completely abolished the atrophic effect of TGF-β. Finally, the inhibition of these canonical and non-canonical pathways did not decrease the ROS increment, while the inhibition of ROS production entirely abolished the phosphorylation of Smad3, ERK1/2 and JNK1/2. These results suggest that TGF-β requires Smad3, ERK1/2 and JNK1/2 activation to produce skeletal muscle atrophy. Moreover, the induction of ROS by TGF-β is an upstream event to canonical and non-canonical pathways.

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Angiotensin (1-7) Decreases Myostatin-Induced NF-κB Signaling and Skeletal Muscle Atrophy

International Journal of Molecular Sciences ◽

10.3390/ijms21031167 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1167 ◽

Cited By ~ 2

Author(s):

Javier Aravena ◽

Johanna Abrigo ◽

Francisco Gonzalez ◽

Francisco Aguirre ◽

Andrea Gonzalez ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Renin Angiotensin System ◽

Ubiquitin Proteasome System ◽

Skeletal Muscle Atrophy ◽

Gene Expressions ◽

Protein Levels ◽

Mas Receptor ◽

Signaling Activation ◽

Species Production

Myostatin is a myokine that regulates muscle function and mass, producing muscle atrophy. Myostatin induces the degradation of myofibrillar proteins, such as myosin heavy chain or troponin. The main pathway that mediates protein degradation during muscle atrophy is the ubiquitin proteasome system, by increasing the expression of atrogin-1 and MuRF-1. In addition, myostatin activates the NF-κB signaling pathway. Renin–angiotensin system (RAS) also regulates muscle mass. Angiotensin (1-7) (Ang-(1-7)) has anti-atrophic properties in skeletal muscle. In this paper, we evaluated the effect of Ang-(1-7) on muscle atrophy and signaling induced by myostatin. The results show that Ang-(1-7) prevented the decrease of the myotube diameter and myofibrillar protein levels induced by myostatin. Ang-(1-7) also abolished the increase of myostatin-induced reactive oxygen species production, atrogin-1, MuRF-1, and TNF-α gene expressions and NF-κB signaling activation. Ang-(1-7) inhibited the activity mediated by myostatin through Mas receptor, as is demonstrated by the loss of all Ang-(1-7)-induced effects when the Mas receptor antagonist A779 was used. Our results show that the effects of Ang-(1-7) on the myostatin-dependent muscle atrophy and signaling are blocked by MK-2206, an inhibitor of Akt/PKB. Together, these data indicate that Ang-(1-7) inhibited muscle atrophy and signaling induced by myostatin through a mechanism dependent on Mas receptor and Akt/PKB.

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Protective Effect of Pyropia yezoensis Peptide on Dexamethasone-Induced Myotube Atrophy in C2C12 Myotubes

Marine Drugs ◽

10.3390/md17050284 ◽

2019 ◽

Vol 17 (5) ◽

pp. 284 ◽

Cited By ~ 4

Author(s):

Min-Kyeong Lee ◽

Jeong-Wook Choi ◽

Youn Hee Choi ◽

Taek-Jeong Nam

Keyword(s):

Skeletal Muscle ◽

Growth Factor ◽

Signaling Pathway ◽

Muscle Atrophy ◽

Skeletal Muscle Atrophy ◽

C2c12 Myotubes ◽

Protective Effects ◽

Factor I ◽

Igf I ◽

Foxo Signaling Pathway

Dexamethasone (DEX), a synthetic glucocorticoid, causes skeletal muscle atrophy. This study examined the protective effects of Pyropia yezoensis peptide (PYP15) against DEX-induced myotube atrophy and its association with insulin-like growth factor-I (IGF-I) and the Akt/mammalian target of rapamycin (mTOR)-forkhead box O (FoxO) signaling pathway. To elucidate the molecular mechanisms underlying the effects of PYP15 on DEX-induced myotube atrophy, C2C12 myotubes were treated for 24 h with 100 μM DEX in the presence or absence of 500 ng/mL PYP15. Cell viability assays revealed no PYP15 toxicity in C2C12 myotubes. PYP15 activated the insulin-like growth factor-I receptor (IGF-IR) and Akt-mTORC1 signaling pathway in DEX-induced myotube atrophy. In addition, PYP15 markedly downregulated the nuclear translocation of transcription factors FoxO1 and FoxO3a, and inhibited 20S proteasome activity. Furthermore, PYP15 inhibited the autophagy-lysosomal pathway in DEX-stimulated myotube atrophy. Our findings suggest that PYP15 treatment protected against myotube atrophy by regulating IGF-I and the Akt-mTORC1-FoxO signaling pathway in skeletal muscle. Therefore, PYP15 treatment appears to exert protective effects against skeletal muscle atrophy.

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Transient changes of transforming growth factor-β expression in the small intestine of the pig in association with weaning

British Journal Of Nutrition ◽

10.1079/bjn20041302 ◽

2005 ◽

Vol 93 (1) ◽

pp. 37-45 ◽

Cited By ~ 19

Author(s):

Jie Mei ◽

Ruo-Jun Xu

Keyword(s):

Small Intestine ◽

Growth Factor ◽

Western Blot ◽

Intestinal Mucosa ◽

Blot Analysis ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Intestinal Villus ◽

Weaning Pigs ◽

Tgf Β1

It is well known that early weaning causes marked changes in intestinal structure and function, and transforming growth factor-β (TGF-β) is believed to play an important regulatory role in post-weaning adaptation of the small intestine. The present study examined the distribution and expression intensity of TGF-β in the small intestinal mucosa of pre- and post-weaning pigs using a specific immunostaining technique and Western blot analysis. The level of TGF-β in the intestinal mucosa, as estimated by Western blot analysis, did not change significantly during weaning. However, when examined by the immunostaining technique, TGF-β1 (one of the TGF-β isoforms dominantly expressed in the tissue) at the intestinal villus epithelium, particularly at the apical membrane of the epithelium, decreased significantly 4 d after weaning, while the staining intensity increased significantly at the intestinal crypts compared with that in pre-weaning pigs. These changes were transient, with the immunostaining intensity for TGF-β1 at the intestinal villi and the crypts returning to the pre-weaning level by 8 d post-weaning. The transient decrease in TGF-β1 level at the intestinal villus epithelium was associated with obvious intestinal villus atrophy and marked reduction of mucosal digestive enzyme activities. Furthermore, the number of leucocytes staining positively for TGF-β1 increased significantly in the pig intestinal lamina propria 4 d after weaning. These findings strongly suggest that TGF-β plays an important role in the post-weaning adaptation process in the intestine of the pig.

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Insulin-like growth factor I slows the rate of denervation induced skeletal muscle atrophy

Neuromuscular Disorders ◽

10.1016/j.nmd.2004.10.013 ◽

2005 ◽

Vol 15 (2) ◽

pp. 139-146 ◽

Cited By ~ 36

Author(s):

Thea Shavlakadze ◽

Jason D. White ◽

Marilyn Davies ◽

Joseph F.Y. Hoh ◽

Miranda D. Grounds

Keyword(s):

Skeletal Muscle ◽

Growth Factor ◽

Muscle Atrophy ◽

Skeletal Muscle Atrophy ◽

Insulin Like Growth Factor ◽

Factor I ◽

Growth Factor I

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Antenatal glucocorticoids counteract LPS changes in TGF-β pathway and caveolin-1 in ovine fetal lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00251.2012 ◽

2013 ◽

Vol 304 (6) ◽

pp. L438-L444 ◽

Cited By ~ 24

Author(s):

Jennifer J. P. Collins ◽

Steffen Kunzmann ◽

Elke Kuypers ◽

Matthew W. Kemp ◽

Christian P. Speer ◽

...

Keyword(s):

Growth Factor ◽

Western Blot ◽

Transforming Growth Factor ◽

Fetal Lung ◽

Tissue Growth ◽

Caveolin 1 ◽

Protein Levels ◽

Smad2 Phosphorylation ◽

Ovine Fetal ◽

Tgf Β1

Inflammation and antenatal glucocorticoids, the latter given to mothers at risk for preterm birth, affect lung development and may contribute to the development of bronchopulmonary dysplasia (BPD). The effects of the combined exposures on inflammation and antenatal glucocorticoids on transforming growth factor (TGF)-β signaling are unknown. TGF-β and its downstream mediators are implicated in the etiology of BPD. Therefore, we asked whether glucocorticoids altered intra-amniotic lipopolysaccharide (LPS) effects on TGF-β expression, its signaling molecule phosphorylated sma and mothers against decapentaplegic homolog 2 (pSmad2), and the downstream mediators connective tissue growth factor (CTGF) and caveolin-1 (Cav-1). Ovine singleton fetuses were randomized to receive either an intra-amniotic injection of LPS and/or maternal betamethasone (BTM) intramuscularly 7 and/or 14 days before delivery at 120 days gestational age (GA; term = 150 days GA). Saline was used for controls. Protein levels of TGF-β1 and -β2 were measured by ELISA. Smad2 phosphorylation was assessed by immunohistochemistry and Western blot. CTGF and Cav-1 mRNA and protein levels were determined by RT-PCR and Western blot. Free TGF-β1 and -β2 and total TGF-β1 levels were unchanged after LPS and/or BTM exposure, although total TGF-β2 increased in animals exposed to BTM 7 days before LPS. pSmad2 immunostaining increased 7 days after LPS exposure although pSmad2 protein expression did not increase. Similarly, CTGF mRNA and protein levels increased 7 days after LPS exposure as Cav-1 mRNA and protein levels decreased. BTM exposure before LPS prevented CTGF induction and Cav-1 downregulation. This study demonstrated that the intrauterine inflammation-induced TGF-β signaling can be inhibited by antenatal glucocorticoids in fetal lungs.

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