Interrelations of myogenic response, progressive atrophy of muscle fibers, and cell death in denervated skeletal muscle
Interrelations of myogenic response, progressive atrophy of muscle fibers, and cell death in denervated skeletal muscle
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DOI：
10.1002/ar.1155
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发表时间：
2001-10-01
影响因子：
--
通讯作者：
Carlson, BM
中科院分区：
文献类型：
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作者：
Borisov, AB;Dedkov, EI;Carlson, BM
关于失神经肌肉中代偿性肌生成的再激活的时间过程和结构动力学、其起始细胞机制以及该过程与失神经后萎缩进展之间的关系知之甚少。本研究的目的是探讨失神经肌肉肌源性反应的时间和空间模式与肌纤维进行性萎缩之间的相互关系。另一个目的是研究是否重新激活的肌肉发生与失神经支配的肌肉细胞的分化状态和死亡的不稳定。目前尚不清楚肌纤维萎缩是否是激活肌源性反应的主要因素，细胞萎缩的水平与其激活相关，以及肌源性的起始和强度是否取决于局部和个体纤维间萎缩变化的异质性。出于这个原因，我们的目的也是确定与肌源性反应激活相关的失神经肌肉纤维的萎缩和退行性变化的水平。我们发现，大鼠胫骨前肌和趾长伸肌肌再生的重新激活开始于神经切断后的第10-21天，在萎缩达到高级水平之前，在组织中发现死细胞之前很久。新肌纤维的形成在去神经支配后2至4个月达到最大值，并随着进行性去神经后萎缩而逐渐减少。肌源性反应是双相的，包括两个不同的过程。第一个过程类似于正常肌肉发育过程中第二代和第三代肌管的形成，并在去神经支配的前2个月占主导地位。在此期间，活化的卫星细胞在活的分化的肌纤维上形成新的肌管。失神经支配1月和2月肌的大多数子肌管在快型母肌纤维表面发育，部分新生肌纤维表达慢型肌球蛋白。一些快型亲本纤维对胚胎异肌球蛋白呈弱阳性，或更罕见的中度阳性。这表明肌生成的再激活也可能取决于纤维类型。失神经肌肉的萎缩程度、分化肌纤维表型的不稳定性和单个纤维的退行性变化是非常不均匀的。第一种类型的肌源性反应主要与平均和高于平均水平的萎缩纤维相关。经历较小程度萎缩的肌细胞也形成子纤维，尽管发生率较低。我们没有发现新形成的纤维的大小和母体纤维的萎缩程度之间有任何相关性。地形分布的新的肌管在中腹部赤道部分的外周和中央区域的早期阶段神经横断后表明，肌发生的第一种类型的肌肉的神经控制的损失的全身反应。这些数据表明，肌源性反应的激活不依赖于细胞死亡和变性过程本身。第二种类型的肌生成是典型的再生反应，主要发生在由死肌纤维的基底层包围的空间内。不同大小的肌细胞易发生变性和死亡，这表明失神经肌肉中的细胞死亡与肌细胞萎缩的程度无关。再生过程经常导致异常肌细胞的发育，这些异常肌细胞分支或形成小簇。神经切断后2至4个月，丢失纤维的替代被激活，即，主要发生在失神经支配后萎缩的晚期，此时细胞死亡成为萎缩过程的促成因素。在长期失神经肌肉，第一和第二类型的myogenesisocur同时，和地形分布的生肌反应变得更加异质性比在第一周后去神经。因此，我们的数据表明，差异的时间和空间表达的两种模式的肌肉发生在失神经支配的肌肉，似乎是由不同的监管机制在postdenervation期间。Anat Rec 264：203-218，2001年。(C)2001 Wiley-Liss，Inc.
Little is known concerning the time-course and structural dynamics of reactivation of compensatory myogenesis in denervated muscle, its initiating cellular mechanisms, and the relationship between this process and the progression of postdenervation atrophy. The purpose of this study was to investigate the interrelations between temporal and spatial patterns of the myogenic response in denervated muscle and progressive atrophy of muscle fibers. Another objective was to study whether reactivation of myogenesis correlates with destabilization of the differentiated state and death of denervated muscle cells. It has remained unclear whether muscle fiber atrophy was the primary factor activating the myogenic response, what levels of cellular atrophy were associated with its activation, and whether the initiation and intensity of myogenesis depended on the local and individual heterogeneity of atrophic changes among fibers. For this reason, our objective was also to identify the levels of atrophic and degenerative changes in denervated muscle fibers that are correlated with activation of the myogenic response. We found that the reactivation of myogenesis in the tibialis anterior and extensor digitorum longus muscles of the rat starts between days 10-21 following nerve transection, before atrophy has attained advanced level, long before dead cells are found in the tissue. Formation of new muscle fibers reaches its maximum between 2 and 4 months following denervation and gradually decreases with progressive postdenervation atrophy. The myogenic response is biphasic and includes two distinct processes. The first process resembles the formation of secondary and tertiary generations of myotubes during normal muscle development and dominates during the first 2 months of denervation. During this period, activated satellite cells form new myotubes on live differentiated muscle fibers. Most of the daughter myotubes in 1- and 2-month denervated muscle develop on the surface of fast type parent muscle fibers, and some of the newly formed muscle fibers express slow myosin. Some fast type parent fibers are weakly or, more rarely, moderately immunopositive for embryonic isomyosin. This indicates that reactivation of myogenesis may also depend on the fiber type. The level of atrophy, destabilization of the differentiated myofiber phenotype, and degenerative changes of individual fibers in denervated muscle are very heterogeneous. The myogenic response of the first type is associated predominantly with fibers of average and higher than average levels of atrophy. Muscle cells that undergo a lesser degree of atrophy also form daughter fibers, although with a lower incidence. We did not find any correlation between the size of newly formed fibers and the level of atrophy of parent fibers. The topographical distribution of new myotubes both in the peripheral and central areas of the mid-belly equatorial sections at the early stages following nerve transection indicates that myogenesis of the first type represents a systemic reaction of muscle to the loss of neural control. These data indicate that activation of the myogenic response does not depend on cell death and degenerative processes per se. The second type of myogenesis is a typical regenerative reaction that occurs mainly within the spaces surrounded by the basal laminae of dead muscle fibers. Myocytes of different sizes are susceptible to degeneration and death, which indicates that cell death in denervated muscle does not correlate with levels of muscle cell atrophy.The regenerative process frequently results in development of abnormal muscle cells that branch or form small clusters. Replacement of lost fibers becomes activated between 2 and 4 months following nerve transection, i.e., mainly at advanced stages of postdenervation atrophy, when cell death becomes a contributing factor of the atrophic process. In long-term denervated muscle, the first and second types of myogenesisoccur concurrently, and the topographical distribution of the myogenic response becomes more heterogeneous than during the first weeks following denervation. Thus, our data demonstrate differential temporal and spatial expression of two patterns of myogenesis in denervated muscle that appear to be controlled by different regulatory mechanisms during the postdenervation period. Anat Rec 264:203-218, 2001. (C) 2001 Wiley-Liss, Inc.