Hamstring contractures in children with spastic cerebral palsy result from a stiffer extracellular matrix and increased in vivo sarcomere length
Hamstring contractures in children with spastic cerebral palsy result from a stiffer extracellular matrix and increased in vivo sarcomere length
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DOI：
10.1113/jphysiol.2010.203364
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发表时间：
2011-05-15
影响因子：
5.5
通讯作者：
Lieber, Richard L.
中科院分区：
文献类型：
--
作者：
Smith, Lucas R.;Lee, Ki S.;Lieber, Richard L.
脑瘫 (CP) 是由发育中的大脑中的上运动神经元 (UMN) 损伤引起的。引起痉挛的 UMN 病变的继发性是肌肉的病理反应，即挛缩。然而，肌肉内增加被动机械刚度并因此导致挛缩的元素尚不清楚。使用 CP 儿科患者 (n = 33) 和对照患者 (n = 19) 的腿筋肌肉活检，我们研究了蛋白质、细胞、组织和结构水平的被动机械特性，以确定导致挛缩的因素。肌联蛋白亚型（肌肉细胞内的主要承载蛋白）在 CP 中未发生改变。相应地，单个肌纤维的被动力学没有改变。然而，CP 肌束（其构成 ECM 中包含纤维）比对照肌束更硬。这与通过羟脯氨酸测定和免疫组织化学观察到的 CP 肌肉胶原蛋白含量的增加相对应。手术期间测量的 CP 肌肉的体内肌节长度明显长于对照肌肉的预测值。增加的组织硬度和增加的肌节长度的组合相互作用以大大增加体内挛缩组织的硬度。这些发现提供的证据表明，挛缩的形成不是细胞水平硬化的结果，而是由于胶原蛋白增加和体内肌节长度增加导致ECM硬化导致更高的被动应力。
Cerebral palsy (CP) results from an upper motoneuron (UMN) lesion in the developing brain. Secondary to the UMN lesion, which causes spasticity, is a pathological response by muscle - namely, contracture. However, the elements within muscle that increase passive mechanical stiffness, and therefore result in contracture, are unknown. Using hamstring muscle biopsies from pediatric patients with CP (n = 33) and control (n = 19) patients we investigated passive mechanical properties at the protein, cellular, tissue and architectural levels to identify the elements responsible for contracture. Titin isoform, the major load-bearing protein within muscle cells, was unaltered in CP. Correspondingly, the passive mechanics of individual muscle fibres were not altered. However, CP muscle bundles, which include fibres in their constituent ECM, were stiffer than control bundles. This corresponded to an increase in collagen content of CP muscles measured by hydroxyproline assay and observed using immunohistochemistry. In vivo sarcomere length of CP muscle measured during surgery was significantly longer than that predicted for control muscle. The combination of increased tissue stiffness and increased sarcomere length interact to increase stiffness greatly of the contracture tissue in vivo. These findings provide evidence that contracture formation is not the result of stiffening at the cellular level, but stiffening of the ECM with increased collagen and an increase of in vivo sarcomere length leading to higher passive stresses.