title: Cardiac sympathetic neurons provide trophic signal to the heart via β2-adrenoceptor-dependent regulation of proteolysis.
abstract: OBJECTIVE
  Increased cardiac sympathetic neuron (SN) activity has been associated with pathologies such as heart failure and hypertrophy, suggesting that cardiac innervation regulates cardiomyocyte trophism. Whether continuous input from the SNs is required for the maintenance of the cardiomyocyte size has not been determined thus far.
  
  
  RESULTS
  To address the role of cardiac innervation in cardiomyocyte size regulation, we monitored the effect of pharmacological sympathetic denervation in mice on cardiac structure, function, and signalling from 24 h to 30 days in the absence of other pathological stimuli. SN ablation caused an immediate reduction in the cardiomyocyte size with minimal consequences on the resting contractile function. Atrophic remodelling was mediated by the ubiquitin-proteasome system through FOXO-dependent early induction of the muscle-specific E3 ubiquitin ligases Atrogin-1/MAFbx and MuRF1, which was followed by activation of the autophagy-lysosome system. MuRF1 was found to be determinant in denervation atrophy as remodelling did not develop in denervated MuRF1 knock-out (KO) hearts. These effects were caused by decreased basal stimulation of cardiomyocyte β2-adrenoceptor (AR), as atrophy was prevented by treatment of denervated mice with the β2-AR agonist clenbuterol. Consistent with these data, we also observed that β2-AR KO mice showed cardiac atrophy at rest.
  
  
  CONCLUSIONS
  Cardiac SNs are strong regulators of the cardiomyocyte size via β2-AR-dependent repression of proteolysis, demonstrating that the neuro-cardiac axis operates constitutively for the determination of the physiological cardiomyocyte size. These results are of great clinical relevance given the role of β-AR in cardiovascular diseases and their modulation in therapy.
authors.affiliation: Department of Biomedical Sciences,  University of Padova, Viale G. Colombo 3, Padova 35121,  Italy.
authors.forename: Tania
authors.initials: T
authors.lastname: Zaglia
authors.forename: Giulia
authors.initials: G
authors.lastname: Milan
authors.forename: Mauro
authors.initials: M
authors.lastname: Franzoso
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertaggia
authors.forename: Nicola
authors.initials: N
authors.lastname: Pianca
authors.forename: Eleonora
authors.initials: E
authors.lastname: Piasentini
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Voltarelli
authors.forename: David
authors.initials: D
authors.lastname: Chiavegato
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brum
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.forename: Stefano
authors.initials: S
authors.lastname: Schiaffino
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.forename: Marco
authors.initials: M
authors.lastname: Mongillo
mesh_terms: D000818:Animals; D001284:Atrophy; D001343:Autophagy; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D006321:Heart / Q000294:innervation*; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000502:physiology; D032383:Myocytes, Cardiac / Q000473:pathology*; D009638:Norepinephrine / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D044843:SKP Cullin F-Box Protein Ligases / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009124:Muscle Proteins; D011506:Proteins; D018343:Receptors, Adrenergic, beta-2; D000070584:Tripartite Motif Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D009638:Norepinephrine