Format

Send to

Choose Destination
Physiol Rep. 2016 May;4(10). pii: e12791. doi: 10.14814/phy2.12791.

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

Author information

1
Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan.
2
Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Orthodontics, Tsurumi University School of Dental Medicine, Yokohama, Japan.
3
Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Pediatric Dentistry, Tsurumi University School of Dental Medicine, Yokohama, Japan.
4
Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Periodontology, Tsurumi University School of Dental Medicine, Yokohama, Japan.
5
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
6
Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
7
Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan okumura-s@tsurumi-u.ac.jp.

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.

KEYWORDS:

Beta‐adrenoceptor; hypertrophy; signal transduction

PMID:
27207782
PMCID:
PMC4886163
DOI:
10.14814/phy2.12791
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center