Graduate School of Biomedical Sciences, University of Maine, Orono, Maine, United States of America.
PLoS Biol. 2012;10(10):e1001409. doi: 10.1371/journal.pbio.1001409. Epub 2012 Oct 23.
Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex- or integrin alpha7-deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction with integrin alpha6 to reduce muscle degeneration. Taken together, these results define a novel cell adhesion pathway that may have future therapeutic relevance for a broad spectrum of muscular dystrophies.
肌肉萎缩症是常见的、目前无法治愈的疾病。其中一部分肌肉萎缩症是由于将肌肉纤维连接到其周围细胞外基质微环境的复合物中的基因中断引起的。细胞-基质黏附物是生理条件的精细传感器，并介导允许细胞适应变化条件的反应。因此，寻找未来治疗应用目标的一种方法是鉴定介导体内这些动态、适应性反应的细胞黏附途径。我们发现，烟酰胺核糖激酶 2b 介导的 NAD+生物合成，作为肌肉纤维-细胞外基质黏附的小分子激动剂，可纠正缺乏肌营养不良蛋白聚糖复合物或整合素 alpha7 的主要成分的斑马鱼的肌肉萎缩表型。外源性 NAD+或 NAD+的维生素前体可减少肌肉纤维退化，并导致肌肉萎缩胚胎的逃避反应明显加快。在这个新的细胞黏附途径中，NAD+下游的细胞黏附蛋白桩蛋白的过表达可减少整合素受体完整的斑马鱼的肌肉退化，但不能改善运动能力。该途径的激活可显著增加层粘连蛋白的组织，层粘连蛋白是细胞外基质基底膜的主要成分。我们的结果表明，NAD+的主要保护作用源自基底膜的变化，因为野生型基底膜足以增加肌肉萎缩纤维对损伤的弹性。令人惊讶的是，NAD+补充可改善肌营养不良蛋白聚糖复合物或整合素 alpha7 缺失的斑马鱼的肌肉萎缩，这表明存在另一种将肌肉纤维锚定到基底膜的层粘连蛋白受体复合物。我们发现整合素 alpha6 参与了该途径，但整合素 alpha7 或肌营养不良蛋白聚糖复合物与整合素 alpha6 一起是减少肌肉退化所必需的。总之，这些结果定义了一种新的细胞黏附途径，它可能对广泛的肌肉萎缩症具有未来的治疗相关性。
