title: Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy.
abstract: OBJECTIVE
  To determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for human Duchenne muscular dystrophy.
  
  
  RESULTS
  Replacement fibrosis in mdx hearts gradually increased with age, suggesting a gradual loss of cardiomyocytes. Echocardiography and intra-left ventricular haemodynamic measurements detected baseline cardiac dysfunction in mdx mice at ≥8 months. However, a reduction of cardiac beta-adrenergic response to isoproterenol (ISO) was already present in mdx mice at 4 months. Ventricular myocytes (VMs) isolated from 4- and 8-month-old mdx mice had greater baseline contractile function {fractional shortening, [Ca(2+)]i, and sarcoplasmic reticulum (SR) Ca(2+) content} and ICa-L than age-matched control VMs and than myocytes isolated from 2-month-old mdx mice. ISO increased myocyte function in the VMs of 4- and 8-month-old mdx mice to the same level as in age-matched control VMs. In the VMs of 12-month-old mdx mice, ISO failed to increase myocyte function to the level in VMs of 12-month-old control mice and could not further increaseICa-L. No differences were observed in the expression of Cav1.2α1c, Cav1.2β1, Cav1.2β2, sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA), and the Na(+)/Ca(2+) exchanger. In contrast, total ryanodine receptor 2 (RyR2) and basal phosphorylation of RyR2, phospholamban, and Cav1.2α1c were found to be increased in hearts of 4-month-old mdx mice; baseline protein kinase A activity was also increased. After ISO treatment, phosphorylation levels were the same in mdx and control hearts. VMs of 4-month-old mdx mice had reduced beta1-adrenergic receptor (β1-AR) density and beta-adrenergic sensitivity.
  
  
  CONCLUSIONS
  In young mdx mice, the myocyte increases its contractile function to compensate for myocyte loss. However, these myocytes with enhanced baseline function have reduced potential for stimulation, decreased β1-AR density/sensitivity, leading to blunted cardiac beta-adrenergic response.
authors.affiliation: Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA School of Medicine, Nankai University, Tianjin, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA College of Biological Sciences, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Ai
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Clinical Sciences, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Shuping
authors.initials: S
authors.lastname: Ge
authors.affiliation: Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China yizhipen@sina.com xchen001@temple.edu.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA Daping Hospital, The Third Military Medical University, Chongqing, China yizhipen@sina.com xchen001@temple.edu.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000367:Age Factors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005355:Fibrosis; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D002118:Calcium; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D018342:Receptors, Adrenergic, beta-1; D019837:Ryanodine Receptor Calcium Release Channel; D000099211:Phospholamban; C514350:CACNA1C protein, mouse
keywords: Beta-adrenergic response; Calcium; Duchenne muscular dystrophy; Heart; Myocyte contraction