Long-Term Blocking of Calcium Channels in mdx Mice Results in Differential Effects on Heart and Skeletal Muscle
Long-Term Blocking of Calcium Channels in mdx Mice Results in Differential Effects on Heart and Skeletal Muscle
复制标题
DOI：
10.1016/j.ajpath.2010.11.027
复制
发表时间：
2011-01-01
影响因子：
6
通讯作者：
Lochmueller, Hanns
中科院分区：
文献类型：
--
作者：
Jorgensen, Louise H.;Blain, Alison;Lochmueller, Hanns
肌营养不良蛋白缺乏症的发病机制是复杂的，不仅涉及肌膜脆性，还涉及钙稳态失调。具体来说，有人提出钙通道通过允许钙离子进入细胞直接引发一系列病理事件。本研究的目的是研究氨基糖苷类抗生素链霉素在mdx杜氏肌营养不良（DMD）小鼠模型发病时长期阻断钙通道的作用。子宫内治疗延迟了年轻mdx小鼠肢体肌肉营养不良症状的发作，但并不能阻止疾病后期发生的变性和再生事件。长期治疗对老年小鼠的肢体肌肉病理、减少纤维化、增加肌上皮稳定性和促进肌肉再生具有积极作用。然而，链霉素治疗对膈肌或心肌没有积极作用，心脏病理恶化。因此，即使在疾病发作之前阻断钙通道也不能预防营养不良，这使得它不太可能成为治疗DMD的方法。这些发现强调了分析治疗小鼠整个生命中的几个时间点以及分析许多组织的重要性，以获得治疗效果的完整图景。（中华病理学杂志，2011,178:273-283;DOI: 10.1016/ j.j ajpath.2010.11.027）
The disease mechanisms underlying dystrophin-deficient muscular dystrophy are complex, involving not only muscle membrane fragility, but also dysregulated calcium homeostasis. Specifically, it has been proposed that calcium channels directly initiate a cascade of pathological events by allowing calcium ions to enter the cell. The objective of this study was to investigate the effect of chronically blocking calcium channels with the aminoglycoside antibiotic streptomycin from onset of disease in the mdx mouse model of Duchenne muscular dystrophy (DMD).Treatment in utero onwards delayed onset of dystrophic symptoms in the limb muscle of young mdx mice, but did not prevent degeneration and regeneration events occurring later in the disease course. Long-term treatment had a positive effect on limb muscle pathology, reduced fibrosis, increased sarcolemmal stability, and promoted muscle regeneration in older mice. However, streptomycin treatment did not show positive effects in diaphragm or heart muscle, and heart pathology was worsened. Thus, blocking calcium channels even before disease onset does not prevent dystrophy, making this an unlikely treatment for DMD. These findings highlight the importance of analyzing several time points throughout the life of the treated mice, as well as analyzing many tissues, to get a complete picture of treatment efficacy. (Am J Pathol 2011, 178:273-283; DOI: 10.1016/j.ajpath.2010.11.027)