Abnormal Skeletal Muscle Regeneration plus Mild Alterations in Mature Fiber Type Specification in Fktn-Deficient Dystroglycanopathy Muscular Dystrophy Mice.
Abnormal Skeletal Muscle Regeneration plus Mild Alterations in Mature Fiber Type Specification in Fktn-Deficient Dystroglycanopathy Muscular Dystrophy Mice.
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DOI：
10.1371/journal.pone.0147049
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Beedle AM
中科院分区：
文献类型：
--
作者：
Foltz SJ;Modi JN;Melick GA;Abousaud MI;Luan J;Fortunato MJ;Beedle AM
糖基化α-肌营养不良聚糖通过肌营养不良蛋白-糖蛋白复合物在细胞外基质蛋白（如层粘连蛋白）和细胞细胞骨架之间提供了必要的联系。在继发性肌营养不良症中，糖基化异常破坏了肌肉结构完整性和信号传导所必需的复杂O-甘露糖聚糖。Fktn缺陷型肌营养不良症小鼠发展为中度至重度肌营养不良症，伴有骨骼肌发育和/或再生缺陷。为了深入了解糖基化α-肌营养不良蛋白聚糖在这些过程中的作用，我们对年轻（2、4和8周龄）和再生肌肉进行了肌纤维分型。在骨骼肌特化过程中Fktn破坏的小鼠（Myf 5/Fktn KO）中，新再生纤维（胚胎肌球蛋白重链阳性）在4周龄时达到峰值，而胫骨前肌（TA）和髂腰肌中的总再生纤维（中央有核）在8周龄时达到最高，表明在4周龄左右达到峰值变性/再生活性。相比之下，成熟的纤维类型规格在2，4和8周龄是相对不变的。在坏死毒素诱导的损伤后14天，Myf 5/Fktn KO（肌肉特异性）和用他莫昔芬后发育诱导的整个动物敲除（Tam/Fktn KO）之间的肌纤维类型存在分歧，尽管在基因缺失后时间相等。值得注意的是，Tam/Fktn KO在损伤后保留了较高水平的胚胎肌球蛋白重链表达，表明分化程序延迟或异常。在损伤后的成熟纤维类型规格中，1型、2a型和2x型纤维的基因型和毒素参数之间存在显著的相互作用，而Myf 5/Fktn和Tam/Fktn研究组在2b型纤维中存在差异。这些数据表明，功能性糖基化α-肌营养不良蛋白聚糖在肌肉再生中具有独特的作用，并可能影响损伤后的纤维类型规格。
Glycosylated α-dystroglycan provides an essential link between extracellular matrix proteins, like laminin, and the cellular cytoskeleton via the dystrophin-glycoprotein complex. In secondary dystroglycanopathy muscular dystrophy, glycosylation abnormalities disrupt a complex O-mannose glycan necessary for muscle structural integrity and signaling. Fktn-deficient dystroglycanopathy mice develop moderate to severe muscular dystrophy with skeletal muscle developmental and/or regeneration defects. To gain insight into the role of glycosylated α-dystroglycan in these processes, we performed muscle fiber typing in young (2, 4 and 8 week old) and regenerated muscle. In mice with Fktn disruption during skeletal muscle specification (Myf5/Fktn KO), newly regenerated fibers (embryonic myosin heavy chain positive) peaked at 4 weeks old, while total regenerated fibers (centrally nucleated) were highest at 8 weeks old in tibialis anterior (TA) and iliopsoas, indicating peak degeneration/regeneration activity around 4 weeks of age. In contrast, mature fiber type specification at 2, 4 and 8 weeks old was relatively unchanged. Fourteen days after necrotic toxin-induced injury, there was a divergence in muscle fiber types between Myf5/Fktn KO (skeletal-muscle specific) and whole animal knockout induced with tamoxifen post-development (Tam/Fktn KO) despite equivalent time after gene deletion. Notably, Tam/Fktn KO retained higher levels of embryonic myosin heavy chain expression after injury, suggesting a delay or abnormality in differentiation programs. In mature fiber type specification post-injury, there were significant interactions between genotype and toxin parameters for type 1, 2a, and 2x fibers, and a difference between Myf5/Fktn and Tam/Fktn study groups in type 2b fibers. These data suggest that functionally glycosylated α-dystroglycan has a unique role in muscle regeneration and may influence fiber type specification post-injury.
影响因子：
3.7
作者：
Kanagawa M;Lu Z;Ito C;Matsuda C;Miyake K;Toda T
通讯作者：
Toda T