Preaged remodeling of myofibrillar cytoarchitecture in skeletal muscle expressing R349P mutant desmin
Preaged remodeling of myofibrillar cytoarchitecture in skeletal muscle expressing R349P mutant desmin
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DOI：
10.1016/j.neurobiolaging.2017.06.001
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发表时间：
2017-10-01
影响因子：
4.2
通讯作者：
Friedrich, Oliver
中科院分区：
文献类型：
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作者：
Diermeier, Stefanie;Buttgereit, Andreas;Friedrich, Oliver
大多数遗传性和获得性肌病的临床特征是进行性肌无力。我们假设单纤维水平上骨骼肌细胞结构的持续紊乱可能先于进行性肌肉无力，并导致进行性肌肉无力。在这里，我们分析了衰老对野生型（wt）、杂合子（het）和纯合子（hom）R349P desmin 敲入小鼠的影响。后者含有最常见的人类 R350P desmin 错义突变的直向同源物。我们定量分析了年轻、中型和老年野生型以及肌间肌病小鼠的快肌和慢肌的亚细胞结构。我们记录了单肌纤维中的多光子二次谐波产生和核荧光信号，以比较所有基因型中与衰老相关的影响。对野生型小鼠的分析表明，随着衰老，快肌纤维的肌原纤维细胞结构保持稳定，而慢肌纤维在衰老过程中表现出结构紊乱。相比之下，所有年龄段的R349P desmin小鼠的快肌纤维和慢肌纤维的肌原纤维细胞结构和核密度均受到严重损害。 Het小鼠仅表现出从成年到早衰年龄组的快肌纤维结构明显退化。我们的研究记录了衰老过程中 3D 肌原纤维结构的正常和 R349P 突变结蛋白相关重塑的明显迹象，这为进行性肌肉无力提供了结构基础。 (C) 2017 Elsevier Inc. 保留所有权利。
The majority of hereditary and acquired myopathies are clinically characterized by progressive muscle weakness. We hypothesized that ongoing derangement of skeletal muscle cytoarchitecture at the single fiber level may precede and be responsible for the progressive muscle weakness. Here, we analyzed the effects of aging in wild-type (wt) and heterozygous (het) and homozygous (hom) R349P desmin knock-in mice. The latter harbor the ortholog of the most frequently encountered human R350P desmin missense mutation. We quantitatively analyzed the subcellular cytoarchitecture of fast- and slow-twitch muscles from young, intermediate, and aged wt as well as desminopathy mice. We recorded multiphoton second harmonic generation and nuclear fluorescence signals in single muscle fibers to compare aging-related effects in all genotypes. The analysis of wt mice revealed that the myofibrillar cytoarchitecture remained stable with aging in fast-twitch muscles, whereas slow-twitch muscle fibers displayed structural derangements during aging. In contrast, the myofibrillar cytoarchitecture and nuclear density were severely compromised in fast- and slow-twitch muscle fibers of hom R349P desmin mice at all ages. Het mice only showed a clear degradation in their fiber structure in fast-twitch muscles from the adult to the presenescent age bin. Our study documents distinct signs of normal and R349P mutant desmin-related remodeling of the 3D myofibrillar architecture during aging, which provides a structural basis for the progressive muscle weakness. (C) 2017 Elsevier Inc. All rights reserved.