title: 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.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ohnuki
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Orthodontics, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Umeki
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Mototani
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Shiozawa
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Pediatric Dentistry, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Nariyama
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Orthodontics, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Periodontology, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kawamura
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Department of Orthodontics, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yagisawa
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Huiling
authors.initials: H
authors.lastname: Jin
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suita
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Yasutake
authors.initials: Y
authors.lastname: Saeki
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: 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.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
mesh_terms: D000318:Adrenergic beta-Agonists / Q000633:toxicity; D000818:Animals; D002976:Clenbuterol / Q000633:toxicity*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006984:Hypertrophy / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009135:Muscular Diseases / Q000139:chemically induced* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D002976:Clenbuterol
keywords: Beta‐adrenoceptor; hypertrophy; signal transduction