Passive stiffness of fibrotic skeletal muscle in mdx mice relates to collagen architecture.
Passive stiffness of fibrotic skeletal muscle in mdx mice relates to collagen architecture.
复制标题
mdx小鼠纤维化骨骼肌的被动僵硬度与胶原蛋白结构有关。
DOI：
10.1113/jp280656
复制
发表时间：
2021-02
影响因子：
5.5
通讯作者：
Smith, Lucas R.
中科院分区：
文献类型：
--
作者：
Brashear, Sarah E.;Wohlgemuth, Ross P.;Gonzalez, Gabriella;Smith, Lucas R.
纤维化在许多骨骼肌病理学中是突出的，包括营养不良、神经障碍、恶病质、慢性肾病、肌肉减少症和代谢障碍。肌肉纤维化与收缩力下降和被动僵硬增加有关，从而限制关节活动度，导致痉挛。然而，更多纤维化物质与功能下降直接相关的假设并不成立。在这里，我们利用新的测量细胞外基质（ECM）和胶原蛋白的结构与ECM形式的肌肉功能。我们使用mdx小鼠（一种纤维化的杜氏肌营养不良模型）和野生型小鼠。在该模型中，趾长伸肌（EDL）肌肉明显僵硬，但总胶原蛋白相似，而比目鱼肌没有改变刚度，但增加胶原蛋白。如通过胶原溶解度所确定的，EDL的刚度与增加的胶原交联相关。使用偏振光显微镜测量ECM对齐显示出在mdx肌肉中分解的野生型肌肉的刚度和对齐之间的稳健关系。直接可视化的大胶原纤维与二次谐波成像显示其相对丰富的僵硬的肌肉。胶原纤维排列与所研究的所有肌肉的刚度有关，并且是ECM参数的肌肉刚度的基于多元线性回归的模型中最重要的因素。这项工作建立了骨骼肌ECM结构的新特征，并为肌肉中胶原纤维的机械功能提供了证据。这一发现表明，增强肌肉功能和过度僵硬的抗纤维化策略应针对大胶原纤维及其排列，而不是总胶原。
Fibrosis is prominent in many skeletal muscle pathologies including dystrophies, neurological disorders, cachexia, chronic kidney disease, sarcopenia and metabolic disorders. Fibrosis in muscle is associated with decreased contractile forces and increased passive stiffness that limits joint mobility leading to contractures. However, the assumption that more fibrotic material is directly related to decreased function has not held true. Here we utilize novel measurement of extracellular matrix (ECM) and collagen architecture to relate ECM form to muscle function. We used mdx mice, a model for Duchenne muscular dystrophy that becomes fibrotic, and wildtype mice. In this model, extensor digitorum longus (EDL) muscle was significantly stiffer, but with similar total collagen, while the soleus muscle did not change stiffness, but increased collagen. The stiffness of the EDL was associated with increased collagen crosslinking as determined by collagen solubility. Measurement of ECM alignment using polarized light microscopy showed a robust relationship between stiffness and alignment for wildtype muscle that broke down in mdx muscles. Direct visualization of large collagen fibres with second harmonic generation imaging revealed their relative abundance in stiff muscles. Collagen fibre alignment was linked to stiffness across all muscles investigated and the most significant factor in a multiple linear regression-based model of muscle stiffness from ECM parameters. This work establishes novel characteristics of skeletal muscle ECM architecture and provides evidence for a mechanical function of collagen fibres in muscle. This finding suggests that anti-fibrotic strategies to enhance muscle function and excessive stiffness should target large collagen fibres and their alignment rather than total collagen.