title: Akt1-mediated fast/glycolytic skeletal muscle growth attenuates renal damage in experimental kidney disease.
abstract: Muscle wasting is frequently observed in patients with kidney disease, and low muscle strength is associated with poor outcomes in these patients. However, little is known about the effects of skeletal muscle growth per se on kidney diseases. In this study, we utilized a skeletal muscle-specific, inducible Akt1 transgenic (Akt1 TG) mouse model that promotes the growth of functional skeletal muscle independent of exercise to investigate the effects of muscle growth on kidney diseases. Seven days after Akt1 activation in skeletal muscle, renal injury was induced by unilateral ureteral obstruction (UUO) in Akt1 TG and wild-type (WT) control mice. The expression of atrogin-1, an atrophy-inducing gene in skeletal muscle, was upregulated 7 days after UUO in WT mice but not in Akt1 TG mice. UUO-induced renal interstitial fibrosis, tubular injury, apoptosis, and increased expression of inflammatory, fibrosis-related, and adhesion molecule genes were significantly diminished in Akt1 TG mice compared with WT mice. An increase in the activating phosphorylation of eNOS in the kidney accompanied the attenuation of renal damage by myogenic Akt1 activation. Treatment with the NOS inhibitor L-NAME abolished the protective effect of skeletal muscle Akt activation on obstructive kidney disease. In conclusion, Akt1-mediated muscle growth reduces renal damage in a model of obstructive kidney disease. This improvement appears to be mediated by an increase in eNOS signaling in the kidney. Our data support the concept that loss of muscle mass during kidney disease can contribute to renal failure, and maintaining muscle mass may improve clinical outcome.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; and.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hanatani
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; and izumiya@kumamoto-u.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; and.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Araki
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; and.
authors.forename: Taku
authors.initials: T
authors.lastname: Rokutanda
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; and.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Department of Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; and.
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology; D006019:Glycolysis; D007249:Inflammation; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D009132:Muscles / Q000473:pathology; D009133:Muscular Atrophy / Q000473:pathology*; D058628:Myofibroblasts / Q000166:cytology; D019331:NG-Nitroarginine Methyl Ester / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010805:Physical Conditioning, Animal; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051437:Renal Insufficiency / Q000503:physiopathology*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism
chemical_list: D052242:Adiponectin; D016207:Cytokines; D009124:Muscle Proteins; D019001:Nitric Oxide Synthase; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019331:NG-Nitroarginine Methyl Ester