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Role of phosphodiesterase 4 expression in the Epac1 signaling‐dependent skeletal muscle hypertrophic action of clenbuterol
Clenbuterol (CB), a selective β (2)‐adrenergic receptor (AR) agonist, induces muscle hypertrophy and counteracts muscle atrophy. However, it is paradoxically less effective in slow‐twitch muscle than in fast‐twitch muscle, though slow‐twitch muscle has a greater density of β‐AR. We recently demonstr...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886163/ https://www.ncbi.nlm.nih.gov/pubmed/27207782 http://dx.doi.org/10.14814/phy2.12791 |
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author | Ohnuki, Yoshiki Umeki, Daisuke Mototani, Yasumasa Shiozawa, Kouichi Nariyama, Megumi Ito, Aiko Kawamura, Naoya Yagisawa, Yuka Jin, Huiling Cai, Wenqian Suita, Kenji Saeki, Yasutake Fujita, Takayuki Ishikawa, Yoshihiro Okumura, Satoshi |
author_facet | Ohnuki, Yoshiki Umeki, Daisuke Mototani, Yasumasa Shiozawa, Kouichi Nariyama, Megumi Ito, Aiko Kawamura, Naoya Yagisawa, Yuka Jin, Huiling Cai, Wenqian Suita, Kenji Saeki, Yasutake Fujita, Takayuki Ishikawa, Yoshihiro Okumura, Satoshi |
author_sort | Ohnuki, Yoshiki |
collection | PubMed |
description | Clenbuterol (CB), a selective β (2)‐adrenergic receptor (AR) agonist, induces muscle hypertrophy and counteracts muscle atrophy. However, it is paradoxically less effective in slow‐twitch muscle than in fast‐twitch muscle, though slow‐twitch muscle has a greater density of β‐AR. We recently demonstrated that Epac1 (exchange protein activated by cyclic AMP [cAMP]1) plays a pivotal role in β (2)‐AR‐mediated masseter muscle hypertrophy through activation of the Akt and calmodulin kinase II (CaMKII)/histone deacetylase 4 (HDAC4) signaling pathways. Here, we investigated the role of Epac1 in the differential hypertrophic effect of CB using tibialis anterior muscle (TA; typical fast‐twitch muscle) and soleus muscle (SOL; typical slow‐twitch muscle) of wild‐type (WT) and Epac1‐null mice (Epac1KO). The TA mass to tibial length (TL) ratio was similar in WT and Epac1KO at baseline and was significantly increased after CB infusion in WT, but not in Epac1KO. The SOL mass to TL ratio was also similar in WT and Epac1KO at baseline, but CB‐induced hypertrophy was suppressed in both mice. In order to understand the mechanism involved, we measured the protein expression levels of β‐AR signaling‐related molecules, and found that phosphodiesterase 4 (PDE4) expression was 12‐fold greater in SOL than in TA. These results are consistent with the idea that increased PDE4‐mediated cAMP hydrolysis occurs in SOL compared to TA, resulting in a reduced cAMP concentration that is insufficient to activate Epac1 and its downstream Akt and CaMKII/HDAC4 hypertrophic signaling pathways in SOL of WT. This scenario can account for the differential effects of CB on fast‐ and slow‐twitch muscles. |
format | Online Article Text |
id | pubmed-4886163 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-48861632016-08-17 Role of phosphodiesterase 4 expression in the Epac1 signaling‐dependent skeletal muscle hypertrophic action of clenbuterol Ohnuki, Yoshiki Umeki, Daisuke Mototani, Yasumasa Shiozawa, Kouichi Nariyama, Megumi Ito, Aiko Kawamura, Naoya Yagisawa, Yuka Jin, Huiling Cai, Wenqian Suita, Kenji Saeki, Yasutake Fujita, Takayuki Ishikawa, Yoshihiro Okumura, Satoshi Physiol Rep Original Research Clenbuterol (CB), a selective β (2)‐adrenergic receptor (AR) agonist, induces muscle hypertrophy and counteracts muscle atrophy. However, it is paradoxically less effective in slow‐twitch muscle than in fast‐twitch muscle, though slow‐twitch muscle has a greater density of β‐AR. We recently demonstrated that Epac1 (exchange protein activated by cyclic AMP [cAMP]1) plays a pivotal role in β (2)‐AR‐mediated masseter muscle hypertrophy through activation of the Akt and calmodulin kinase II (CaMKII)/histone deacetylase 4 (HDAC4) signaling pathways. Here, we investigated the role of Epac1 in the differential hypertrophic effect of CB using tibialis anterior muscle (TA; typical fast‐twitch muscle) and soleus muscle (SOL; typical slow‐twitch muscle) of wild‐type (WT) and Epac1‐null mice (Epac1KO). The TA mass to tibial length (TL) ratio was similar in WT and Epac1KO at baseline and was significantly increased after CB infusion in WT, but not in Epac1KO. The SOL mass to TL ratio was also similar in WT and Epac1KO at baseline, but CB‐induced hypertrophy was suppressed in both mice. In order to understand the mechanism involved, we measured the protein expression levels of β‐AR signaling‐related molecules, and found that phosphodiesterase 4 (PDE4) expression was 12‐fold greater in SOL than in TA. These results are consistent with the idea that increased PDE4‐mediated cAMP hydrolysis occurs in SOL compared to TA, resulting in a reduced cAMP concentration that is insufficient to activate Epac1 and its downstream Akt and CaMKII/HDAC4 hypertrophic signaling pathways in SOL of WT. This scenario can account for the differential effects of CB on fast‐ and slow‐twitch muscles. John Wiley and Sons Inc. 2016-05-20 /pmc/articles/PMC4886163/ /pubmed/27207782 http://dx.doi.org/10.14814/phy2.12791 Text en © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Ohnuki, Yoshiki Umeki, Daisuke Mototani, Yasumasa Shiozawa, Kouichi Nariyama, Megumi Ito, Aiko Kawamura, Naoya Yagisawa, Yuka Jin, Huiling Cai, Wenqian Suita, Kenji Saeki, Yasutake Fujita, Takayuki Ishikawa, Yoshihiro Okumura, Satoshi Role of phosphodiesterase 4 expression in the Epac1 signaling‐dependent skeletal muscle hypertrophic action of clenbuterol |
title | Role of phosphodiesterase 4 expression in the Epac1 signaling‐dependent skeletal muscle hypertrophic action of clenbuterol |
title_full | Role of phosphodiesterase 4 expression in the Epac1 signaling‐dependent skeletal muscle hypertrophic action of clenbuterol |
title_fullStr | Role of phosphodiesterase 4 expression in the Epac1 signaling‐dependent skeletal muscle hypertrophic action of clenbuterol |
title_full_unstemmed | Role of phosphodiesterase 4 expression in the Epac1 signaling‐dependent skeletal muscle hypertrophic action of clenbuterol |
title_short | Role of phosphodiesterase 4 expression in the Epac1 signaling‐dependent skeletal muscle hypertrophic action of clenbuterol |
title_sort | role of phosphodiesterase 4 expression in the epac1 signaling‐dependent skeletal muscle hypertrophic action of clenbuterol |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886163/ https://www.ncbi.nlm.nih.gov/pubmed/27207782 http://dx.doi.org/10.14814/phy2.12791 |
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