title: Akt/mTOR pathway contributes to skeletal muscle anti-atrophic effect of aerobic exercise training in heart failure mice.
abstract: BACKGROUND
  Exercise intolerance is one of the main clinical symptoms of heart failure (HF) and is associated with skeletal muscle wasting due to an imbalance between proteolysis and protein synthesis. In this study, we tested whether aerobic exercise training (AET) would counteract skeletal muscle atrophy by activating IGF-I/Akt/mTOR pathway in HF mice.
  
  
  METHODS
  Sympathetic hyperactivity induced HF mice were assigned into 8-week moderate intensity AET. Untrained wild type and HF mice were used as control. Soleus cross sectional area was evaluated by histochemistry and motor performance by rotarod. 26S proteasome activity was assessed by fluorimetric assay, and components of IGF-I/Akt/mTOR pathway or myostatin pathway by qRT-PCR or immunoblotting. A different subset of mice was used to evaluate the relative contribution of mTOR inhibition (rapamycin) or activation (leucine) on AET-induced changes in muscle mass regulation.
  
  
  RESULTS
  AET prevented exercise intolerance and impaired motor performance in HF mice. These effects were associated with attenuation of soleus atrophy. Rapamycin treatment precluded AET effects on soleus mass in HF mice suggesting the involvement of IGF signaling pathway in this response. In fact, AET increased IGF-I Ea and IGF-I Pan mRNA levels, while it reduced myostatin and Smad2 mRNA levels in HF mice. At protein levels, AET prevented reduced expression levels of IGF-I, pAkt (at basal state), as well as, p4E-BP1 and pP70(S6K) (leucine-stimulated state) in HF mice. Additionally, AET prevented 26S proteasome hyperactivity in HF mice.
  
  
  CONCLUSIONS
  Taken together, our data provide evidence for AET-induced activation of IGF-I/Akt/mTOR signaling pathway counteracting HF-induced muscle wasting.
authors.affiliation: School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Aline V N
authors.initials: AV
authors.lastname: Bacurau
authors.affiliation: School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Paulo R
authors.initials: PR
authors.lastname: Jannig
authors.affiliation: Department of Biosciences, Federal University of São Paulo, Santos, Brazil.
authors.forename: Wilson M A M
authors.initials: WM
authors.lastname: de Moraes
authors.affiliation: School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Telma F
authors.initials: TF
authors.lastname: Cunha
authors.affiliation: Department of Biosciences, Federal University of São Paulo, Santos, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Medeiros
authors.affiliation: Institute Pasteur-Cenci Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Barberi
authors.affiliation: School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Marcele A
authors.initials: MA
authors.lastname: Coelho
authors.affiliation: School of Arts, Sciences, Humanities, University of São Paulo, SP, Brazil.
authors.forename: Reury F P
authors.initials: RF
authors.lastname: Bacurau
authors.affiliation: School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ugrinowitsch
authors.affiliation: Institute Pasteur-Cenci Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Musarò
authors.affiliation: School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil. Electronic address: pcbrum@usp.br.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brum
mesh_terms: D000818:Animals; D006333:Heart Failure / Q000378:metabolism* / Q000628:therapy; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism* / Q000517:prevention & control; D010805:Physical Conditioning, Animal / Q000379:methods / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Aerobic exercise training; Atrophy; Heart failure; IGF-I/Akt/mTOR; Skeletal muscle