Role of phosphodiesterase 4 expression in the Epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol.

Abstract

Clenbuterol (CB), a selective β2-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 β2-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.

• Authors: Yoshiki Ohnuki, Daisuke Umeki, Yasumasa Mototani, Kouichi Shiozawa, Megumi Nariyama, Aiko Ito, Naoya Kawamura, Yuka Yagisawa, Huiling Jin, Wenqian Cai, Kenji Suita, Yasutake Saeki, Takayuki Fujita, Yoshihiro Ishikawa, Satoshi Okumura
• Journal: Physiological reports (Physiol Rep) Vol. 4 Issue 10 (May 2016) ISSN: 2051-817X [Electronic] United States
• PMID: 27207782 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Chemical References

• Adrenergic beta-Agonists
• Epac protein, mouse
• Guanine Nucleotide Exchange Factors
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Clenbuterol

Topics

• Adrenergic beta-Agonists (toxicity)
• Animals
• Clenbuterol (toxicity)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (biosynthesis)
• Gene Expression Regulation, Enzymologic
• Guanine Nucleotide Exchange Factors (metabolism)
• Hypertrophy (chemically induced, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Mice, Knockout
• Muscle, Skeletal (drug effects, metabolism)
• Muscular Diseases (chemically induced, metabolism)
• Signal Transduction (drug effects, physiology)