Voiland School of Chemical Engineering and Bioengineering, Washington State University , Pullman, Washington.
Department of Animal Sciences, Washington State University , Pullman, Washington.
J Appl Physiol (1985). 2017 Dec 1;123(6):1698-1707. doi: 10.1152/japplphysiol.00744.2016. Epub 2017 Aug 31.
Limb-girdle muscular dystrophy (LGMD) 2i results from mutations in fukutin-related protein and aberrant α-dystroglycan glycosylation. Although this significantly compromises muscle function and ambulation, the comprehensive characteristics of contractile dysfunction are unknown. Therefore, we quantified the in situ contractile properties of the medial gastrocnemius in young adult P448L mice, an affected muscle of a novel model of LGMD2i. Normalized maximal twitch force, tetanic force, and power were significantly smaller in P448L mice, compared with sex-matched, wild-type mice. These differences were consistent with the replacement of contractile fibers by passive tissue. The shape of the active force-length relationships were similar in both groups, regardless of sex, consistent with an intact sarcomeric structure in P448L mice. Passive force-length curves normalized to maximal isometric force were steeper in P448L mice, and passive elements contribute disproportionately more to total contractile force in P448L mice. Sex differences were mostly noted in the force-velocity curves, as normalized values for maximal and optimal velocities were significantly slower in P448L males, compared with wild-type, but not in P448L females. This suggests that the dystrophic phenotype, which may include possible changes in cross-bridge kinetics and fiber-type proportions, progresses more quickly in P448L males. These results together indicate that active force and power generation are compromised in both sexes of P448L mice, while passive forces increase. More importantly, the results identified several functional markers of disease pathophysiology that could aid in developing and assessment of novel therapeutics for LGMD2i and possibly other dystroglycanopathies as well. NEW & NOTEWORTHY Comprehensive assessments of muscle contractile function have, until now, never been performed in an animal model for any dystroglycanopathy. This study suggests that skeletal muscle contractile properties are significantly compromised in a recently developed model for limb-girdle muscular dystrophy 2i, the P448L mouse. It further identifies novel pathological markers of muscle function that are suitable for developing therapeutics and for better understanding of disease pathogenesis.
肢带型肌营养不良症 2i（LGMD2i）是由与福ukin 相关蛋白的突变和异常的α-肌聚糖糖基化引起的。尽管这显著损害了肌肉功能和行走能力，但收缩功能障碍的综合特征尚不清楚。因此，我们定量分析了年轻成年 P448L 小鼠内侧腓肠肌的原位收缩特性，P448L 小鼠是一种新型 LGMD2i 模型中的受影响肌肉。与性别匹配的野生型小鼠相比，P448L 小鼠的最大抽搐力、强直力和功率明显较小。这些差异与收缩纤维被被动组织替代一致。两组的主动力-长度关系的形状相似，无论性别如何，这表明 P448L 小鼠的肌节结构完整。P448L 小鼠的被动力-长度曲线相对于最大等长力归一化后更陡峭，并且被动元素在 P448L 小鼠中的总收缩力中占比不成比例。性别差异主要在力-速度曲线中观察到，与野生型相比，P448L 雄性的最大和最佳速度的归一化值明显较慢，但 P448L 雌性则不然。这表明，可能包括横桥动力学和纤维类型比例变化的营养不良表型在 P448L 雄性中进展更快。这些结果共同表明，P448L 小鼠的两性的主动力和功率生成都受到了损害，而被动力增加。更重要的是，这些结果确定了几种疾病病理生理学的功能标志物，这些标志物可用于开发和评估 LGMD2i 及其他可能的肌聚糖病的新型治疗方法。
新的和值得注意的是，到目前为止，在任何肌聚糖病的动物模型中，都从未进行过肌肉收缩功能的综合评估。这项研究表明，在最近开发的肢带型肌营养不良症 2i（P448L 小鼠）模型中，骨骼肌收缩特性受到显著损害。它进一步确定了肌肉功能的新的病理标志物，这些标志物适合开发治疗方法，并更好地了解疾病发病机制。
