与 MYMK 相关的凯里-费内曼-齐特综合征尽管有明显的肥大,但肌核结构异常和肌纤维收缩能力受损。

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Hannah F Dugdale, Yotam Levy, Heinz Jungbluth, Anders Oldfors, Julien Ochala
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引用次数: 0

摘要

凯里-费恩曼-齐特综合征(CFZS)是一种罕见的常染色体隐性遗传病,由编码蛋白 Myomaker 的 MYMK 基因座突变引起。Myomaker 蛋白对于肌肉祖细胞在生长发育过程中的融合和同时捐献肌核至关重要。令人震惊的是,在人类中,MYMK 基因突变似乎会促使肌纤维肥大,但矛盾的是,它会诱发全身肌肉无力。由于潜在的细胞机制仍未探明,本研究旨在通过结合肌纤维深度分型和蛋白质组学分析来深入了解这一机制。因此,我们分离了 CFZS 患者的单个肌纤维,并进行了力学、三维形态学和蛋白质组分析。与健康人相比,CFZS 患者的肌纤维比对照组大约 4 倍,拥有的肌核比对照组多约 2 倍,导致肌核域体积不成比例地增大。与对照组肌肉细胞相比,CFZS 患者肌纤维的肌核结构域体积更大,但细胞内在的发力能力却更小。我们的补充蛋白质组分析表明,233 种蛋白质发生了重塑,尤其是那些与细胞呼吸相关的蛋白质。总之,我们的研究结果表明,CFZS 患者的肌生成器具有一定的功能,但相关的核增生最终可能导致 CFZS 患者出现无功能性肥大和能量相关机制的改变。所有这些都可能是导致 CFZS 患者肌无力的原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Aberrant myonuclear domains and impaired myofiber contractility despite marked hypertrophy in MYMK-related, Carey-Fineman-Ziter Syndrome.

Carey Fineman Ziter Syndrome (CFZS) is a rare autosomal recessive disease caused by mutations in the MYMK locus which encodes the protein, myomaker. Myomaker is essential for fusion and concurrent myonuclei donation of muscle progenitors during growth and development. Strikingly, in humans, MYMK mutations appear to prompt myofiber hypertrophy but paradoxically, induce generalised muscle weakness. As the underlying cellular mechanisms remain unexplored, the present study aimed to gain insights by combining myofiber deep-phenotyping and proteomic profiling. Hence, we isolated individual muscle fibers from CFZS patients and performed mechanical, 3D morphological and proteomic analyses. Myofibers from CFZS patients were ~ 4x larger than controls and possessed ~ 2x more myonuclei than those from healthy subjects, leading to disproportionally larger myonuclear domain volumes. These greater myonuclear domain sizes were accompanied by smaller intrinsic cellular force generating-capacities in myofibers from CFZS patients than in control muscle cells. Our complementary proteomic analyses indicated remodelling in 233 proteins particularly those associated with cellular respiration. Overall, our findings suggest that myomaker is somewhat functional in CFZS patients, but the associated nuclear accretion may ultimately lead to non-functional hypertrophy and altered energy-related mechanisms in CFZS patients. All of these are likely contributors of the muscle weakness experienced by CFZS patients.

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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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