School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.
Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
Acta Neuropathol Commun. 2024 May 24;12(1):80. doi: 10.1186/s40478-024-01783-2.
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.
卡里·芬曼·齐特综合征（CFZS）是一种罕见的常染色体隐性疾病，由编码肌形成蛋白（myomaker）的 MYMK 基因座突变引起。肌形成蛋白对于生长和发育过程中肌肉祖细胞的融合和同时核捐赠是必不可少的。引人注目的是，在人类中，MYMK 突变似乎促使肌纤维肥大，但矛盾的是，却导致了全身性肌肉无力。由于潜在的细胞机制仍未被探索，本研究旨在通过结合肌纤维深度表型分析和蛋白质组学分析来获得深入了解。因此，我们从 CFZS 患者中分离出单个肌纤维，并进行了机械、3D 形态学和蛋白质组学分析。CFZS 患者的肌纤维比对照组大 4 倍，比健康受试者的肌纤维多 2 倍核，导致不成比例的更大的核区体积。与 CFZS 患者的肌纤维相比，这些更大的核区体积伴随着较小的固有细胞产生能力。我们的互补蛋白质组学分析表明，233 种蛋白质，特别是那些与细胞呼吸相关的蛋白质发生了重塑。总的来说，我们的发现表明肌形成蛋白在 CFZS 患者中具有一定的功能，但相关的核积累最终可能导致 CFZS 患者出现非功能性肥大和改变的能量相关机制。所有这些都可能是 CFZS 患者肌肉无力的原因。
