TGF-β requires the activation of canonical and non-canonical signalling pathways to induce skeletal muscle atrophy
-
Johanna Ábrigo
Abstract
The 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 C2C12 myotubes. 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.
Acknowledgements
This study was supported by research grants from the National Fund for Science and Technology Development, [FONDECYT 1161646 (CCV), 1161288 (FS), 1161438 (CV)]; Programa de Cooperación Científica ECOS-CONICYT [C16S02]; the Millennium Institute on Immunology and Immunotherapy [P09-016-F (CCV-FS-CR)]; and the Universidad Andrés Bello-Dirección de Investigación [741-15/N (CCV-FS-CR)]. J. Ábrigo would like to thank Conicyt for providing a PhD Scholarship [21161353]. C.V. acknowledges support from BASAL Grant [FB0807], MECESUP PMI-UAB [1301], and the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie Grant Agreement [734801].
References
Abrigo, J., Morales, M.G., Simon, F., Cabrera, D., Di Capua, G., and Cabello-Verrugio, C. (2015). Apocynin inhibits the upregulation of TGF-β1 expression and ROS production induced by TGF-beta in skeletal muscle cells. Phytomedicine 22, 885–93.10.1016/j.phymed.2015.06.011Search in Google Scholar PubMed
Abrigo, J., Rivera, J.C., Simon, F., Cabrera, D., and Cabello-Verrugio, C. (2016). Transforming growth factor type β (TGF-β) requires reactive oxygen species to induce skeletal muscle atrophy. Cell Signal. 28, 366–376.10.1016/j.cellsig.2016.01.010Search in Google Scholar PubMed
Acuna, M.J., Pessina, P., Olguin, H., Cabrera, D., Vio, C.P., Bader, M., Munoz-Canoves, P., Santos, R.A., Cabello-Verrugio, C., and Brandan, E. (2014). Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling. Hum. Mol. Genet. 23, 1237–1249.10.1093/hmg/ddt514Search in Google Scholar PubMed
Argiles, J.M., Busquets, S., Felipe, A., and Lopez-Soriano, F.J. (2006). Muscle wasting in cancer and ageing: cachexia versus sarcopenia. Adv. Gerontol. 18, 39–54.10.1007/978-90-481-9713-2_2Search in Google Scholar
Barbieri, E. and Sestili, P. (2012). Reactive oxygen species in skeletal muscle signaling. J. Signal. Transduct. 2012, 982794.10.1155/2012/982794Search in Google Scholar PubMed PubMed Central
Bennett, B.L., Sasaki, D.T., Murray, B.W., O’Leary, E.C., Sakata, S.T., Xu, W., Leisten, J.C., Motiwala, A., Pierce, S., Satoh, Y., et al. (2001). SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. USA 98, 13681–13686.10.1073/pnas.251194298Search in Google Scholar PubMed PubMed Central
Bernasconi, P., Di Blasi, C., Mora, M., Morandi, L., Galbiati, S., Confalonieri, P., Cornelio, F., and Mantegazza, R. (1999). Transforming growth factor-β1 and fibrosis in congenital muscular dystrophies. Neuromuscul. Disord. 9, 28–33.10.1016/S0960-8966(98)00093-5Search in Google Scholar
Brandan, E., Cabello-Verrugio, C., and Vial, C. (2008). Novel regulatory mechanisms for the proteoglycans decorin and biglycan during muscle formation and muscular dystrophy. Matrix Biol. 27, 700–708.10.1016/j.matbio.2008.07.004Search in Google Scholar PubMed
Brink, M., Price, S.R., Chrast, J., Bailey, J.L., Anwar, A., Mitch, W.E., and Delafontaine, P. (2001). Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I. Endocrinology 142, 1489–1496.10.1210/endo.142.4.8082Search in Google Scholar PubMed
Burks, T.N. and Cohn, R.D. (2011). Role of TGF-beta signaling in inherited and acquired myopathies. Skelet. Muscle 1, 19.10.1186/2044-5040-1-19Search in Google Scholar PubMed PubMed Central
Burks, T.N., Andres-Mateos, E., Marx, R., Mejias, R., Van Erp, C., Simmers, J.L., Walston, J.D., Ward, C.W., and Cohn, R.D. (2011). Losartan restores skeletal muscle remodeling and protects against disuse atrophy in sarcopenia. Sci. Transl. Med. 3, 82ra37.10.1126/scitranslmed.3002227Search in Google Scholar PubMed PubMed Central
Cabello-Verrugio, C. and Brandan, E. (2007). A novel modulatory mechanism of transforming growth factor-beta signaling through decorin and LRP-1. J. Biol. Chem. 282, 18842–18850.10.1074/jbc.M700243200Search in Google Scholar PubMed
Cabello-Verrugio, C., Acuna, M.J., Morales, M.G., Becerra, A., Simon, F., and Brandan, E. (2011). Fibrotic response induced by angiotensin-II requires NAD(P)H oxidase-induced reactive oxygen species (ROS) in skeletal muscle cells. Biochem. Biophys. Res. Commun. 410, 665–670.10.1016/j.bbrc.2011.06.051Search in Google Scholar PubMed
Cabello-Verrugio, C., Cordova, G., and Salas, J.D. (2012a). Angiotensin II: role in skeletal muscle atrophy. Curr. Protein Pept. Sci. 13, 560–569.10.2174/138920312803582933Search in Google Scholar PubMed
Cabello-Verrugio, C., Santander, C., Cofre, C., Acuna, M.J., Melo, F., and Brandan, E. (2012b). The internal region leucine-rich repeat 6 of decorin interacts with low density lipoprotein receptor-related protein-1, modulates transforming growth factor (TGF)-β-dependent signaling, and inhibits TGF-β-dependent fibrotic response in skeletal muscles. J. Biol. Chem. 287, 6773–6787.10.1074/jbc.M111.312488Search in Google Scholar PubMed PubMed Central
Cabello-Verrugio, C., Morales, M.G., Rivera, J.C., Cabrera, D., and Simon, F. (2015). Renin-angiotensin system: an old player with novel functions in skeletal muscle. Med. Res. Rev. 35, 437–463.10.1002/med.21343Search in Google Scholar PubMed
Cencetti, F., Bernacchioni, C., Nincheri, P., Donati, C., and Bruni, P. (2010). Transforming growth factor-beta1 induces transdifferentiation of myoblasts into myofibroblasts via up-regulation of sphingosine kinase-1/S1P3 axis. Mol. Biol. Cell. 21, 1111–1124.10.1091/mbc.e09-09-0812Search in Google Scholar PubMed PubMed Central
Chomczynski, P. and Sacchi, N. (1987). Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159.10.1016/0003-2697(87)90021-2Search in Google Scholar
Cofre, C., Acuna, M.J., Contreras, O., Morales, M.G., Riquelme, C., Cabello-Verrugio, C., and Brandan, E. (2015). Transforming growth factor type-beta inhibits Mas receptor expression in fibroblasts but not in myoblasts or differentiated myotubes; Relevance to fibrosis associated to muscular dystrophies. Biofactors 41, 111–120.10.1002/biof.1208Search in Google Scholar PubMed
Cooney, R.N., Kimball, S.R., and Vary, T.C. (1997). Regulation of skeletal muscle protein turnover during sepsis: mechanisms and mediators. Shock 7, 1–16.10.1097/00024382-199701000-00001Search in Google Scholar PubMed
Derynck, R. and Zhang, Y.E. (2003). Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425, 577–584.10.1038/nature02006Search in Google Scholar PubMed
Droguett, R., Cabello-Verrugio, C., Santander, C., and Brandan, E. (2010). TGF-β receptors, in a Smad-independent manner, are required for terminal skeletal muscle differentiation. Exp. Cell Res. 316, 2487–2503.10.1016/j.yexcr.2010.04.031Search in Google Scholar PubMed
Eley, H.L., Russell, S.T., and Tisdale, M.J. (2008). Mechanism of attenuation of muscle protein degradation induced by tumor necrosis factor-α and angiotensin II by β-hydroxy-β-methylbutyrate. Am. J. Physiol. Endocrinol. Metab. 295, E1417–E1426.10.1152/ajpendo.90567.2008Search in Google Scholar PubMed
Evans, W.J., Morley, J.E., Argiles, J., Bales, C., Baracos, V., Guttridge, D., Jatoi, A., Kalantar-Zadeh, K., Lochs, H., Mantovani, G., et al. (2008). Cachexia: a new definition. Clin. Nutr. 27, 793–799.10.1016/j.clnu.2008.06.013Search in Google Scholar PubMed
Glass, D.J. (2005). Skeletal muscle hypertrophy and atrophy signaling pathways. Int. J. Biochem. Cell Biol. 37, 1974–1984.10.1016/j.biocel.2005.04.018Search in Google Scholar PubMed
Greco, S.H., Tomkotter, L., Vahle, A.K., Rokosh, R., Avanzi, A., Mahmood, S.K., Deutsch, M., Alothman, S., Alqunaibit, D., Ochi, A., et al. (2015). TGF-β blockade reduces mortality and metabolic changes in a validated murine model of pancreatic cancer cachexia. PLoS One 10, e0132786.10.1371/journal.pone.0132786Search in Google Scholar PubMed PubMed Central
Guadagnin, E., Narola, J., Bonnemann, C.G., and Chen, Y.W. (2015). Tyrosine 705 phosphorylation of STAT3 is associated with phenotype severity in TGFβ1 transgenic mice. Biomed. Res. Int. 2015, 843743.10.1155/2015/843743Search in Google Scholar PubMed PubMed Central
Huang, Z., Chen, D., Zhang, K., Yu, B., Chen, X., and Meng, J. (2007). Regulation of myostatin signaling by c-Jun N-terminal kinase in C2C12 cells. Cell Signal. 19, 2286–2295.10.1016/j.cellsig.2007.07.002Search in Google Scholar PubMed
Ishitobi, M., Haginoya, K., Zhao, Y., Ohnuma, A., Minato, J., Yanagisawa, T., Tanabu, M., Kikuchi, M., and Iinuma, K. (2000). Elevated plasma levels of transforming growth factor β1 in patients with muscular dystrophy. Neuroreport 11, 4033–4035.10.1097/00001756-200012180-00026Search in Google Scholar PubMed
Jackman, R.W. and Kandarian, S.C. (2004). The molecular basis of skeletal muscle atrophy. Am J. Physiol. Cell Physiol. 287, C834–843.10.1152/ajpcell.00579.2003Search in Google Scholar PubMed
Kefaloyianni, E., Gaitanaki, C., and Beis, I. (2006). ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-κB transactivation during oxidative stress in skeletal myoblasts. Cell Signal. 18, 2238–2251.10.1016/j.cellsig.2006.05.004Search in Google Scholar PubMed
Kollias, H.D. and McDermott, J.C. (2008). Transforming growth factor-β and myostatin signaling in skeletal muscle. J. Appl. Physiol. 104, 579–587.10.1152/japplphysiol.01091.2007Search in Google Scholar PubMed
Massague, J. (2012). TGFβ signalling in context. Nat. Rev. Mol. Cell Biol. 13, 616–630.10.1038/nrm3434Search in Google Scholar PubMed PubMed Central
Mauro, A., Ciccarelli, C., De Cesaris, P., Scoglio, A., Bouche, M., Molinaro, M., Aquino, A., and Zani, B.M. (2002). PKCα-mediated ERK, JNK and p38 activation regulates the myogenic program in human rhabdomyosarcoma cells. J. Cell Sci. 115, 3587–3599.10.1242/jcs.00037Search in Google Scholar PubMed
Mendias, C.L., Gumucio, J.P., Davis, M.E., Bromley, C.W., Davis, C.S., and Brooks, S.V. (2012). Transforming growth factor-β induces skeletal muscle atrophy and fibrosis through the induction of atrogin-1 and scleraxis. Muscle Nerve 45, 55–59.10.1002/mus.22232Search in Google Scholar PubMed PubMed Central
Meneses, C., Morales, M.G., Abrigo, J., Simon, F., Brandan, E., and Cabello-Verrugio, C. (2015). The angiotensin-(1-7)/Mas axis reduces myonuclear apoptosis during recovery from angiotensin II-induced skeletal muscle atrophy in mice. Pflüger’s Arch. 467, 1975–1984.10.1007/s00424-014-1617-9Search in Google Scholar PubMed
Miro, O., Pedrol, E., Cebrian, M., Masanes, F., Casademont, J., Mallolas, J., and Grau, J.M. (1997). Skeletal muscle studies in patients with HIV-related wasting syndrome. J. Neurol. Sci. 150, 153–159.10.1016/S0022-510X(97)00079-8Search in Google Scholar
Morales, M.G., Vazquez, Y., Acuna, M.J., Rivera, J.C., Simon, F., Salas, J.D., Alvarez Ruf, J., Brandan, E., and Cabello-Verrugio, C. (2012). Angiotensin II-induced pro-fibrotic effects require p38MAPK activity and transforming growth factor β1 expression in skeletal muscle cells. Int. J. Biochem. Cell Biol. 44, 1993–2002.10.1016/j.biocel.2012.07.028Search in Google Scholar PubMed
Morales, M.G., Abrigo, J., Meneses, C., Simon, F., Cisternas, F., Rivera, J.C., Vazquez, Y., and Cabello-Verrugio, C. (2014). The Ang-(1-7)/Mas-1 axis attenuates the expression and signalling of TGF-β1 induced by AngII in mouse skeletal muscle. Clin. Sci. 127, 251–264.10.1042/CS20130585Search in Google Scholar PubMed
Morris, R.T., Spangenburg, E.E., and Booth, F.W. (2004). Responsiveness of cell signaling pathways during the failed 15-day regrowth of aged skeletal muscle. J. Appl. Physiol. 96, 398–404.10.1152/japplphysiol.00454.2003Search in Google Scholar PubMed
Narola, J., Pandey, S.N., Glick, A., and Chen, Y.W. (2013). Conditional expression of TGF-β1 in skeletal muscles causes endomysial fibrosis and myofibers atrophy. PLoS One 8, e79356.10.1371/journal.pone.0079356Search in Google Scholar PubMed PubMed Central
Sartori, R., Milan, G., Patron, M., Mammucari, C., Blaauw, B., Abraham, R., and Sandri, M. (2009). Smad2 and 3 transcription factors control muscle mass in adulthood. Am. J. Physiol. Cell Physiol. 296, C1248–C1257.10.1152/ajpcell.00104.2009Search in Google Scholar PubMed
Schmittgen, T.D., Zakrajsek, B.A., Mills, A.G., Gorn, V., Singer, M.J., and Reed, M.W. (2000). Quantitative reverse transcription-polymerase chain reaction to study mRNA decay: comparison of endpoint and real-time methods. Anal. Biochem. 285, 194–204.10.1006/abio.2000.4753Search in Google Scholar PubMed
Tando, T., Hirayama, A., Furukawa, M., Sato, Y., Kobayashi, T., Funayama, A., Kanaji, A., Hao, W., Watanabe, R., Morita, M., et al. (2016). Smad2/3 are required for immobilization-induced skeletal muscle atrophy. J. Biol. Chem. 291, 12184–12194.10.1074/jbc.M115.680579Search in Google Scholar PubMed PubMed Central
ten Dijke, P. and Hill, C.S. (2004). New insights into TGF-β-Smad signalling. Trends Biochem. Sci. 29, 265–273.10.1016/j.tibs.2004.03.008Search in Google Scholar PubMed
Tisdale, M.J. (2009). Mechanisms of cancer cachexia. Physiol. Rev. 89, 381–410.10.1152/physrev.00016.2008Search in Google Scholar PubMed
Trendelenburg, A.U., Meyer, A., Rohner, D., Boyle, J., Hatakeyama, S., and Glass, D.J. (2009). Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am. J. Physiol. Cell Physiol. 296, C1258–C1270.10.1152/ajpcell.00105.2009Search in Google Scholar PubMed
Winer, J., Jung, C.K., Shackel, I., and Williams, P.M. (1999). Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal. Biochem. 270, 41–49.10.1006/abio.1999.4085Search in Google Scholar PubMed
Zhang, P., Chen, X., and Fan, M. (2007). Signaling mechanisms involved in disuse muscle atrophy. Med. Hypotheses 6, 310–321.10.1016/j.mehy.2006.11.043Search in Google Scholar PubMed
Supplemental Material:
The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2017-0217).
©2018 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Reviews
- Host target-based approaches against arboviral diseases
- The role of microRNAs in chronic respiratory disease: recent insights
- Research Articles/Short Communications
- Protein Structure and Function
- Selection of an Anticalin® against the membrane form of Hsp70 via bacterial surface display and its theranostic application in tumour models
- Cell Biology and Signaling
- TGF-β requires the activation of canonical and non-canonical signalling pathways to induce skeletal muscle atrophy
- Impact of protamine I on colon cancer proliferation, invasion, migration, diagnosis and prognosis
- Mechanism and dynamics of INPP5E transport into and inside the ciliary compartment
- Novel Techniques
- A novel design of HA-coated nanoparticles co-encapsulating plasmid METase and 5-Fu shows enhanced application in targeting gastric cancer stem cells
Articles in the same Issue
- Frontmatter
- Reviews
- Host target-based approaches against arboviral diseases
- The role of microRNAs in chronic respiratory disease: recent insights
- Research Articles/Short Communications
- Protein Structure and Function
- Selection of an Anticalin® against the membrane form of Hsp70 via bacterial surface display and its theranostic application in tumour models
- Cell Biology and Signaling
- TGF-β requires the activation of canonical and non-canonical signalling pathways to induce skeletal muscle atrophy
- Impact of protamine I on colon cancer proliferation, invasion, migration, diagnosis and prognosis
- Mechanism and dynamics of INPP5E transport into and inside the ciliary compartment
- Novel Techniques
- A novel design of HA-coated nanoparticles co-encapsulating plasmid METase and 5-Fu shows enhanced application in targeting gastric cancer stem cells