title: Chronic heart failure reduces Akt phosphorylation in human skeletal muscle: relationship to muscle size and function.
abstract: Patients with chronic heart failure (HF) frequently lose muscle mass and function during the course of the disease. A reduction in anabolic stimuli to the muscle has been put forth as a potential mechanism underlying these alterations. The present study examined the hypothesis that skeletal muscle tissue from HF patients would show reduced IGF-1 expression and phosphorylation of signaling molecules downstream of receptor activation. To isolate the unique effect of HF on these variables, we limited the confounding effects of muscle disuse and/or acute disease exacerbation by recruiting controls (n = 11) with similar physical activity levels as HF patients (n = 11) and by testing patients at least 6 mo following any bouts of disease exacerbation/hospitalization. IGF-1 expression in skeletal muscle was similar between patients and controls. Despite this, HF patients were characterized by reduced levels of phospho-Akt/Akt (S473; -43%; P < 0.05), whereas no differences were found in total Akt protein content or phospho- or total protein content of mammalian target of rapamycin (mTOR; S2448), glycogen synthase kinase-3β (GSK-3β; S9), eukaryotic translation initiation factor 4E binding protein-1 (eIF4E-BP; T37/46), p70 ribosomal S6 kinase (p70 S6K; T389), or eIF2Bε (S540). Reduced phospho-Akt/Akt levels and phospho-mTOR/mTOR were related to decreased skeletal muscle myosin protein content (r = 0.602; P < 0.02) and knee extensor isometric torque (r = 0.550; P < 0.05), respectively. Because patients and controls were similar for age, muscle mass, and physical activity, we ascribe the observed alterations in Akt phosphorylation and its relationship to myosin protein content to the unique effects of the HF syndrome.
authors.affiliation: Health Science Research Facility, Univ. of Vermont, Burlington, VT 05405, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Toth
authors.forename: Kimberly
authors.initials: K
authors.lastname: Ward
authors.forename: Jos
authors.initials: J
authors.lastname: van der Velden
authors.forename: Mark S
authors.initials: MS
authors.lastname: Miller
authors.forename: Peter
authors.initials: P
authors.lastname: Vanburen
authors.forename: Martin M
authors.initials: MM
authors.lastname: Lewinter
authors.forename: Philip A
authors.initials: PA
authors.lastname: Ades
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D015153:Blotting, Western; D001823:Body Composition / Q000502:physiology; D018797:Cell Cycle Proteins; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019415:Torque
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3