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Licensed Unlicensed Requires Authentication Published by De Gruyter November 15, 2017

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

Johanna Ábrigo , Fabian Campos , Felipe Simon , Claudia Riedel , Daniel Cabrera , Cristian Vilos and Claudio Cabello-Verrugio EMAIL logo
From the journal Biological Chemistry


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.


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].


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Received: 2017-8-11
Accepted: 2017-11-3
Published Online: 2017-11-15
Published in Print: 2018-2-23

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