title: Constitutive activation of CaMKKα signaling is sufficient but not necessary for mTORC1 activation and growth in mouse skeletal muscle.
abstract: Skeletal muscle loading/overload stimulates the Ca²⁺-activated, serine/threonine kinase Ca²⁺/calmodulin-dependent protein kinase kinase-α (CaMKKα); yet to date, no studies have examined whether CaMKKα regulates muscle growth. The purpose of this study was to determine if constitutive activation of CaMKKα signaling could stimulate muscle growth and if so whether CaMKKα is essential for this process. CaMKKα signaling was selectively activated in mouse muscle via expression of a constitutively active form of CaMKKα using in vivo electroporation. After 2 wk, constitutively active CaMKKα expression increased muscle weight (~10%) and protein content (~10%), demonstrating that activation of CaMKKα signaling can stimulate muscle growth. To determine if active CaMKKα expression stimulated muscle growth via increased mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis, [³H]phenylalanine incorporation into proteins was assessed with or without the mTORC1 inhibitor rapamycin. Constitutively active CaMKKα increased protein synthesis ~60%, and this increase was prevented by rapamycin, demonstrating a critical role for mTORC1 in this process. To determine if CaMKKα is essential for growth, muscles from CaMKKα knockout mice were stimulated to hypertrophy via unilateral ablation of synergist muscles (overload). Surprisingly, compared with wild-type mice, muscles from CaMKKα knockout mice exhibited greater growth (~15%) and phosphorylation of the mTORC1 substrate 70-kDa ribosomal protein S6 kinase (Thr³⁸⁹; ~50%), demonstrating that CaMKKα is not essential for overload-induced mTORC1 activation or muscle growth. Collectively, these results demonstrate that activation of CaMKKα signaling is sufficient but not necessary for activation of mTORC1 signaling and growth in mouse skeletal muscle.
authors.affiliation: Departments of Kinesiology, Biochemistry and Molecular Biology, and Physiology, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina.
authors.forename: Jeremie L A
authors.initials: JL
authors.lastname: Ferey
authors.affiliation: Departments of Kinesiology, Biochemistry and Molecular Biology, and Physiology, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Brault
authors.affiliation: Departments of Kinesiology, Biochemistry and Molecular Biology, and Physiology, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina.
authors.forename: Cheryl A S
authors.initials: CA
authors.lastname: Smith
authors.affiliation: Departments of Kinesiology, Biochemistry and Molecular Biology, and Physiology, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina witczakc@ecu.edu.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Witczak
mesh_terms: D055011:Ablation Techniques / Q000009:adverse effects; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003433:Crosses, Genetic; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006984:Hypertrophy; D066298:In Vitro Techniques; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D024510:Muscle Development / Q000187:drug effects; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D046912:Multiprotein Complexes; D009124:Muscle Proteins; D047428:Protein Kinase Inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517699:Camkk1 protein, mouse
keywords: calcium; kinase; protein degradation; protein synthesis; synergist ablation