title: Molecular basis for the improvement in muscle metaboreflex and mechanoreflex control in exercise-trained humans with chronic heart failure.
abstract: Previous studies have demonstrated that muscle mechanoreflex and metaboreflex controls are altered in heart failure (HF), which seems to be due to changes in cyclooxygenase (COX) pathway and changes in receptors on afferent neurons, including transient receptor potential vanilloid type-1 (TRPV1) and cannabinoid receptor type-1 (CB1). The purpose of the present study was to test the hypotheses: 1) exercise training (ET) alters the muscle metaboreflex and mechanoreflex control of muscle sympathetic nerve activity (MSNA) in HF patients. 2) The alteration in metaboreflex control is accompanied by increased expression of TRPV1 and CB1 receptors in skeletal muscle. 3) The alteration in mechanoreflex control is accompanied by COX-2 pathway in skeletal muscle. Thirty-four consecutive HF patients with ejection fractions <40% were randomized to untrained (n = 17; 54 ± 2 yr) or exercise-trained (n = 17; 56 ± 2 yr) groups. MSNA was recorded by microneurography. Mechanoreceptors were activated by passive exercise and metaboreceptors by postexercise circulatory arrest (PECA). COX-2 pathway, TRPV1, and CB1 receptors were measured in muscle biopsies. Following ET, resting MSNA was decreased compared with untrained group. During PECA (metaboreflex), MSNA responses were increased, which was accompanied by the expression of TRPV1 and CB1 receptors. During passive exercise (mechanoreflex), MSNA responses were decreased, which was accompanied by decreased expression of COX-2, prostaglandin-E2 receptor-4, and thromboxane-A2 receptor and by decreased in muscle inflammation, as indicated by increased miRNA-146 levels and the stable NF-κB/IκB-α ratio. In conclusion, ET alters muscle metaboreflex and mechanoreflex control of MSNA in HF patients. This alteration with ET is accompanied by alteration in TRPV1 and CB1 expression and COX-2 pathway and inflammation in skeletal muscle.
authors.affiliation: Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil;
authors.forename: Ligia M
authors.initials: LM
authors.lastname: Antunes-Correa
authors.affiliation: Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil;
authors.forename: Thais S
authors.initials: TS
authors.lastname: Nobre
authors.affiliation: Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil;
authors.forename: Raphaela V
authors.initials: RV
authors.lastname: Groehs
authors.affiliation: Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil;
authors.forename: Maria Janieire N N
authors.initials: MJ
authors.lastname: Alves
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Tiago
authors.initials: T
authors.lastname: Fernandes
authors.affiliation: Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Gisele K
authors.initials: GK
authors.lastname: Couto
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Maria Urbana P B
authors.initials: MU
authors.lastname: Rondon
authors.affiliation: Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil;
authors.forename: Patricia
authors.initials: P
authors.lastname: Oliveira
authors.affiliation: Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil;
authors.forename: Marta
authors.initials: M
authors.lastname: Lima
authors.affiliation: Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil;
authors.forename: Wilson
authors.initials: W
authors.lastname: Mathias
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brum
authors.affiliation: Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil;
authors.forename: Charles
authors.initials: C
authors.lastname: Mady
authors.affiliation: Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil; and.
authors.forename: Dirceu R
authors.initials: DR
authors.lastname: Almeida
authors.affiliation: Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Luciana V
authors.initials: LV
authors.lastname: Rossoni
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Edilamar M
authors.initials: EM
authors.lastname: Oliveira
authors.affiliation: Departament of Medicine (Cardiology) and Physiology, Geffen School of Medicine at University of California, Los Angeles, California.
authors.forename: Holly R
authors.initials: HR
authors.lastname: Middlekauff
authors.affiliation: Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil; School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil; cndnegrao@incor.usp.br.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Negrao
mesh_terms: D000328:Adult; D000368:Aged; D002908:Chronic Disease; D051546:Cyclooxygenase 2 / Q000502:physiology; D005080:Exercise Test; D005081:Exercise Therapy; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology*; D043884:Receptor, Cannabinoid, CB1 / Q000096:biosynthesis; D012018:Reflex / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013318:Stroke Volume / Q000502:physiology; D013564:Sympathetic Nervous System / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000096:biosynthesis
chemical_list: D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D051546:Cyclooxygenase 2
keywords: exercise training; heart failure; mechanoreflex; metaboreflex; muscle sympathetic nervous system