title: Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice.
abstract: Exercise training (ET) is a coadjuvant therapy in preventive cardiology. It delays cardiac dysfunction and exercise intolerance in heart failure (HF); however, the molecular mechanisms underlying its cardioprotection are poorly understood. We tested the hypothesis that ET would prevent Ca(2+) handling abnormalities and ventricular dysfunction in sympathetic hyperactivity-induced HF mice. A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)-adrenoceptor knockout (alpha(2A)/alpha(2C)ARKO) mice with C57BL6/J genetic background (3-5 mo of age) were randomly assigned into untrained and exercise-trained groups. ET consisted of 8-wk swimming session, 60 min, 5 days/wk. Fractional shortening (FS) was assessed by two-dimensional guided M-mode echocardiography. The protein expression of ryanodine receptor (RyR), phospho-Ser(2809)-RyR, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2), Na(+)/Ca(2+) exchanger (NCX), phospholamban (PLN), phospho-Ser(16)-PLN, and phospho-Thr(17)-PLN were analyzed by Western blotting. At 3 mo of age, no significant difference in FS and exercise tolerance was observed between WT and alpha(2A)/alpha(2C)ARKO mice. At 5 mo, when cardiac dysfunction is associated with lung edema and increased plasma norepinephrine levels, alpha(2A)/alpha(2C)ARKO mice presented reduced FS paralleled by decreased SERCA2 (26%) and NCX (34%). Conversely, alpha(2A)/alpha(2C)ARKO mice displayed increased phospho-Ser(16)-PLN (76%) and phospho-Ser(2809)-RyR (49%). ET in alpha(2A)/alpha(2C)ARKO mice prevented exercise intolerance, ventricular dysfunction, and decreased plasma norepinephrine. ET significantly increased the expression of SERCA2 (58%) and phospho-Ser(16)-PLN (30%) while it restored the expression of phospho-Ser(2809)-RyR to WT levels. Collectively, we provide evidence that improved net balance of Ca(2+) handling proteins paralleled by a decreased sympathetic activity on ET are, at least in part, compensatory mechanisms against deteriorating ventricular function in HF.
authors.affiliation: School of Physical Education and Sport, University of São Paulo, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Medeiros
authors.forename: Natale P L
authors.initials: NP
authors.lastname: Rolim
authors.forename: Rodrigo S F
authors.initials: RS
authors.lastname: Oliveira
authors.forename: Kaleizu T
authors.initials: KT
authors.lastname: Rosa
authors.forename: Katt C
authors.initials: KC
authors.lastname: Mattos
authors.forename: Dulce E
authors.initials: DE
authors.lastname: Casarini
authors.forename: Maria Claúdia
authors.initials: MC
authors.lastname: Irigoyen
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Krieger
authors.forename: José Eduardo
authors.initials: JE
authors.lastname: Krieger
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Negrão
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brum
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005081:Exercise Therapy; D017079:Exercise Tolerance; D006333:Heart Failure / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000097:blood; D005082:Physical Exertion; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012107:Research Design; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D018754:Ventricular Dysfunction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D009638:Norepinephrine; D018341:Receptors, Adrenergic, alpha-2; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban; C547769:Adra2a protein, mouse; C547770:Adra2a protein, rat; C547775:Adra2c protein, mouse; C547776:Adra2c protein, rat; C506948:Atp2a2 protein, rat