Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: role of exercise training.
Sympathetic hyperactivity (SH) is a hallmark of heart failure (HF), and several lines of evidence suggest that SH contributes to HF-induced skeletal myopathy. However, little is known about the influence of SH on skeletal muscle morphology and metabolism in a setting of developing HF, taking into consideration muscles with different fiber compositions. The contribution of SH on exercise tolerance and skeletal muscle morphology and biochemistry was investigated in 3- and 7-mo-old mice lacking both alpha(2A)- and alpha(2C)-adrenergic receptor subtypes (alpha(2A)/alpha(2C)ARKO mice) that present SH with evidence of HF by 7 mo. To verify whether exercise training (ET) would prevent skeletal muscle myopathy in advanced-stage HF, alpha(2A)/alpha(2C)ARKO mice were exercised from 5 to 7 mo of age. At 3 mo, alpha(2A)/alpha(2C)ARKO mice showed no signs of HF and preserved exercise tolerance and muscular norepinephrine with no changes in soleus morphology. In contrast, plantaris muscle of alpha(2A)/alpha(2C)ARKO mice displayed hypertrophy and fiber type shift (IIA --> IIX) paralleled by capillary rarefaction, increased hexokinase activity, and oxidative stress. At 7 mo, alpha(2A)/alpha(2C)ARKO mice displayed exercise intolerance and increased muscular norepinephrine, muscular atrophy, capillary rarefaction, and increased oxidative stress. ET reestablished alpha(2A)/alpha(2C)ARKO mouse exercise tolerance to 7-mo-old wild-type levels and prevented muscular atrophy and capillary rarefaction associated with reduced oxidative stress. Collectively, these data provide direct evidence that SH is a major factor contributing to skeletal muscle morphological changes in a setting of developing HF. ET prevented skeletal muscle myopathy in alpha(2A)/alpha(2C)ARKO mice, which highlights its importance as a therapeutic tool for HF.
Bacurau
Aline V N
AV
Escola de Educação Física e Esporte da Universidade de São Paulo, Departamento de Biodinâmica do Movimento do Corpo Humano, Av. Professor Mello Moraes, 65, Butantã, São Paulo 05508-900, Brazil.
Jardim
Maíra A
MA
Ferreira
Julio C B
JC
Bechara
Luiz R G
LR
Bueno
Carlos R
CR
Alba-Loureiro
Tatiana C
TC
Negrao
Carlos E
CE
Casarini
Dulce E
DE
Curi
Rui
R
Ramires
Paulo R
PR
Moriscot
Anselmo S
AS
Brum
Patricia C
PC
D000818:Animals; D002196:Capillaries / Q000473:pathology; D004195:Disease Models, Animal; D017079:Exercise Tolerance / Q000502:physiology; D006333:Heart Failure / Q000473:pathology* / Q000503:physiopathology; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009638:Norepinephrine / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000503:physiopathology*
C547775:Adra2c protein, mouse; D018341:Receptors, Adrenergic, alpha-2; D009638:Norepinephrine