Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany.
J Cell Mol Med. 2012 Dec;16(12):3028-36. doi: 10.1111/j.1582-4934.2012.01630.x.
Progressive cardiomyopathy is a major cause of death in Duchenne muscular dystrophy (DMD) patients. Coupling between Ca(2+) handling and contractile properties in dystrophic hearts is poorly understood. It is also not clear whether developing cardiac failure is dominated by alterations in Ca(2+) pathways or more related to the contractile apparatus. We simultaneously recorded force and Ca(2+) transients in field-stimulated papillary muscles from young (10-14 weeks) wild-type (wt) and dystrophic mdx mice. Force amplitudes were fivefold reduced in mdx muscles despite only 30% reduction in fura-2 ratio amplitudes. This indicated mechanisms other than systolic Ca(2+) to additionally account for force decrements in mdx muscles. pCa-force relations revealed decreased mdx myofibrillar Ca(2+) sensitivity. 'In vitro' motility assays, studied in mdx hearts here for the first time, showed significantly slower sliding velocities. mdx MLC/MHC isoforms were not grossly altered. Dystrophic hearts showed echocardiography signs of early ventricular wall hypertrophy with a significantly enlarged end-diastolic diameter 'in vivo'. However, fractional shortening was still comparable to wt mice. Changes in the contractile apparatus satisfactorily explained force drop in mdx hearts. We give first evidence of early hypertrophy in mdx mice and possible mechanisms for already functional impairment of cardiac muscle in DMD.
进行性心肌病是杜兴肌营养不良症（DMD）患者死亡的主要原因。在营养不良的心脏中，钙处理与收缩性能之间的偶联作用知之甚少。目前尚不清楚心脏衰竭的发展是由钙途径的改变还是更与收缩装置有关。我们同时记录了来自年轻（10-14 周）野生型（wt）和营养不良型 mdx 小鼠的场刺激乳头肌中的力和 Ca（2+）瞬变。尽管 fura-2 比率幅度降低了 30%，但 mdx 肌肉中的力幅度仍降低了五倍。这表明，除了收缩期 Ca（2+）之外，还有其他机制额外导致 mdx 肌肉中的力降低。pCa-力关系表明 mdx 肌球蛋白钙敏感性降低。这里首次在 mdx 心脏中进行的“体外”运动试验表明，滑动速度明显较慢。mdx MLC/MHC 同工型没有明显改变。超声心动图显示，营养不良的心脏出现早期心室壁肥厚的迹象，“体内”舒张末期直径明显增大。然而，缩短分数仍与 wt 小鼠相当。收缩装置的变化充分解释了 mdx 心脏中的力下降。我们首次提供了 mdx 小鼠早期肥大的证据，以及 DMD 中心肌功能障碍的可能机制。
