title: Role of cyclic AMP sensor Epac1 in masseter muscle hypertrophy and myosin heavy chain transition induced by β2-adrenoceptor stimulation.
abstract: The predominant isoform of β-adrenoceptor (β-AR) in skeletal muscle is β2-AR and that in the cardiac muscle is β1-AR. We have reported that Epac1 (exchange protein directly activated by cAMP 1), a new protein kinase A-independent cAMP sensor, does not affect cardiac hypertrophy in response to pressure overload or chronic isoproterenol (isoprenaline) infusion. However, the role of Epac1 in skeletal muscle hypertrophy remains poorly understood. We thus examined the effect of disruption of Epac1, the major Epac isoform in skeletal muscle, on masseter muscle hypertrophy induced by chronic β2-AR stimulation with clenbuterol (CB) in Epac1-null mice (Epac1KO). The masseter muscle weight/tibial length ratio was similar in wild-type (WT) and Epac1KO at baseline and was significantly increased in WT after CB infusion, but this increase was suppressed in Epac1KO. CB treatment significantly increased the proportion of myosin heavy chain (MHC) IIb at the expense of that of MHC IId/x in both WT and Epac1KO, indicating that Epac1 did not mediate the CB-induced MHC isoform transition towards the faster isoform. The mechanism of suppression of CB-mediated hypertrophy in Epac1KO is considered to involve decreased activation of Akt signalling. In addition, CB-induced histone deacetylase 4 (HDAC4) phosphorylation on serine 246 mediated by calmodulin kinase II (CaMKII), which plays a role in skeletal muscle hypertrophy, was suppressed in Epac1KO. Our findings suggest that Epac1 plays a role in β2-AR-mediated masseter muscle hypertrophy, probably through activation of both Akt signalling and CaMKII/HDAC4 signalling.
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, 230-8501, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ohnuki
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, 230-8501, Japan Department of Orthodontics, Tsurumi University School of Dental Medicine, Yokohama, 230-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Umeki
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, 230-8501, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Mototani
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Huiling
authors.initials: H
authors.lastname: Jin
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, 230-8501, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Shiozawa
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suita
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, 230-8501, Japan.
authors.forename: Yasutake
authors.initials: Y
authors.lastname: Saeki
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, 230-8501, Japan Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan okumura-s@tsurumi-u.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006984:Hypertrophy / Q000378:metabolism; D008406:Masseter Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D018995:Myosin Heavy Chains