Skeletal muscle contractile properties in a novel murine model for limb girdle muscular dystrophy 2i.
Skeletal muscle contractile properties in a novel murine model for limb girdle muscular dystrophy 2i.
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肢带型肌营养不良症 2i 新型小鼠模型中的骨骼肌收缩特性。
DOI：
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发表时间：
2017
影响因子：
3.3
通讯作者：
D. C. Lin
中科院分区：
文献类型：
--
作者：
Jordan D Rehwaldt;B. D. Rodgers;D. C. Lin
四肢带状肌营养不良症（LGMD） 2i是由福克汀相关蛋白突变和α-三磷酸糖基化异常引起的。尽管这明显损害了肌肉功能和活动，但收缩功能障碍的综合特征尚不清楚。因此，我们量化了年轻成年小鼠P448L内侧腓肠肌的原位收缩特性，P448L是一种新型LGMD2i模型的受累肌肉。与性别匹配的野生型小鼠相比，P448L小鼠的标准化最大抽搐力、强直力和功率明显更小。这些差异与被动组织替代收缩纤维一致。在两组中，无论性别，活动力-长度关系的形状都是相似的，这与P448L小鼠的完整肌肉结构一致。P448L小鼠的被动力-长度曲线归一化为最大等距力时更陡峭，被动元素对P448L小鼠总收缩力的贡献不成比例地更大。性别差异主要体现在力-速度曲线上，与野生型相比，P448L雄性的最大和最佳速度的归一化值明显慢于野生型，而P448L雌性则没有。这表明营养不良表型在P448L雄性中进展更快，其中可能包括过桥动力学和纤维型比例的变化。这些结果共同表明，在P448L小鼠的两性中，主动力和发电量都受到损害，而被动力则增加。更重要的是，研究结果确定了几种疾病病理生理学的功能标记物，这些标记物可以帮助开发和评估LGMD2i和其他糖营养不良疾病的新疗法。新的和值得注意的是，到目前为止，还没有在任何糖代谢异常的动物模型中进行过肌肉收缩功能的全面评估。这项研究表明，在最近开发的肢带肌营养不良2i模型P448L小鼠中，骨骼肌收缩特性显著受损。它进一步确定了新的肌肉功能病理标记，适合于开发治疗方法和更好地了解疾病的发病机制。
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.
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