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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
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.
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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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