School of Medical Sciences, University of New South Wales , Sidney, New South Wales , Australia.
School of Medicine, Western Sydney University, Penrith, New South Wales , Australia.
Am J Physiol Cell Physiol. 2018 Jun 1;314(6):C662-C674. doi: 10.1152/ajpcell.00161.2017. Epub 2018 Feb 7.
A striking pathological feature of dystrophinopathies is the presence of morphologically abnormal branched skeletal muscle fibers. The deterioration of muscle contractile function in Duchenne muscular dystrophy is accompanied by both an increase in number and complexity of these branched fibers. We propose that when number and complexity of branched fibers reaches a critical threshold, or "tipping point," the branches in and of themselves are the site of contraction-induced rupture. In the present study, we use the dystrophic mdx mouse and littermate controls to study the prediseased dystrophic fast-twitch extensor digitorum longus (EDL) muscle at 2-3 wk, the peak myonecrotic phase at 6-9 wk, and finally, "old," at 58-112 wk. Using a combination of isolated muscle function contractile measurements coupled with single-fiber imaging and confocal microscope imaging of cleared whole muscles, we identified a distinct pathophysiology, acute fiber rupture at branch nodes, which occurs in "old" fast-twitch EDL muscle approaching the end stage of the dystrophinopathy muscle disease, where the EDL muscles are entirely composed of complexed branched fibers. This evidence supports our concept of "tipping point" where the number and extent of fiber branching reach a level where the branching itself terminally compromises muscle function, irrespective of the absence of dystrophin.
肌营养不良症的一个显著病理学特征是存在形态异常的分支骨骼肌纤维。在杜氏肌营养不良症中，肌肉收缩功能的恶化伴随着这些分支纤维数量和复杂性的增加。我们提出，当分支纤维的数量和复杂性达到一个临界阈值或“临界点”时，分支本身就是收缩诱导破裂的部位。在本研究中，我们使用营养不良的 mdx 小鼠及其同窝对照，研究 2-3 周时的预发病变的快速抽搐伸趾长肌（EDL）肌肉、6-9 周时的峰值肌坏死阶段，以及最后，在 58-112 周时的“老年”阶段。我们使用结合了分离肌肉功能收缩测量以及对清除后的整个肌肉进行单纤维成像和共聚焦显微镜成像的方法，鉴定了一种独特的病理生理学，即分支节点处的急性纤维破裂，这种情况发生在接近肌营养不良症肌肉疾病终末期的“老年”快速抽搐 EDL 肌肉中，此时 EDL 肌肉完全由复杂的分支纤维组成。这一证据支持了我们的“临界点”概念，即纤维分支的数量和程度达到了一个水平，分支本身最终会损害肌肉功能，而与是否存在肌营养不良蛋白无关。
