Ying Li1, Shuai Zhang2, Xiaoying Zhang3, Jing Li4, Xiaojie Ai5, Li Zhang6, Daohai Yu7, Shuping Ge8, Yizhi Peng9, Xiongwen Chen10. 1. 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. 2. Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China. 3. Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA. 4. Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA School of Medicine, Nankai University, Tianjin, China. 5. Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA College of Biological Sciences, Shanghai Jiaotong University, Shanghai, China. 6. Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA Drexel University College of Medicine, Philadelphia, PA, USA. 7. Department of Clinical Sciences, Temple University School of Medicine, Philadelphia, PA, USA. 8. Drexel University College of Medicine, Philadelphia, PA, USA. 9. Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China yizhipen@sina.com xchen001@temple.edu. 10. 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.
Abstract
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: To determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for humanDuchenne muscular dystrophy. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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