Ganassi Massimo, Zammit Peter S
King's College London, Randall Centre for Cell and Molecular Biophysics, Guy's Campus, London.
Eur J Transl Myol. 2022 Mar 18;32(1):10064. doi: 10.4081/ejtm.2022.10064.
Neuromuscular disorders are a heterogeneous group of acquired or hereditary conditions that affect striated muscle function. The resulting decrease in muscle strength and motility irreversibly impacts quality of life. In addition to directly affecting skeletal muscle, pathogenesis can also arise from dysfunctional crosstalk between nerves and muscles, and may include cardiac impairment. Muscular weakness is often progressive and paralleled by continuous decline in the ability of skeletal muscle to functionally adapt and regenerate. Normally, the skeletal muscle resident stem cells, named satellite cells, ensure tissue homeostasis by providing myoblasts for growth, maintenance, repair and regeneration. We recently defined 'Satellite Cell-opathies' as those inherited neuromuscular conditions presenting satellite cell dysfunction in muscular dystrophies and myopathies (doi:10.1016/j.yexcr.2021.112906). Here, we expand the portfolio of Satellite Cell-opathies by evaluating the potential impairment of satellite cell function across all 16 categories of neuromuscular disorders, including those with mainly neurogenic and cardiac involvement. We explore the expression dynamics of myopathogenes, genes whose mutation leads to skeletal muscle pathogenesis, using transcriptomic analysis. This revealed that 45% of myopathogenes are differentially expressed during early satellite cell activation (0 - 5 hours). Of these 271 myopathogenes, 83 respond to Pax7, a master regulator of satellite cells. Our analysis suggests possible perturbation of satellite cell function in many neuromuscular disorders across all categories, including those where skeletal muscle pathology is not predominant. This characterisation further aids understanding of pathomechanisms and informs on development of prognostic and diagnostic tools, and ultimately, new therapeutics.
神经肌肉疾病是一组异质性的获得性或遗传性疾病，会影响横纹肌功能。由此导致的肌肉力量和运动能力下降会对生活质量产生不可逆转的影响。除了直接影响骨骼肌外，发病机制还可能源于神经与肌肉之间的功能失调串扰，并且可能包括心脏损害。肌肉无力通常呈进行性发展，同时骨骼肌在功能上适应和再生的能力也会持续下降。正常情况下，骨骼肌中的常驻干细胞，即卫星细胞，通过提供成肌细胞来实现生长、维持、修复和再生，从而确保组织的稳态。我们最近将“卫星细胞病”定义为那些在肌肉营养不良症和肌病中表现出卫星细胞功能障碍的遗传性神经肌肉疾病（doi:10.1016/j.yexcr.2021.112906）。在此，我们通过评估所有16类神经肌肉疾病中卫星细胞功能的潜在损害，包括那些主要累及神经和心脏的疾病，来扩展卫星细胞病的范畴。我们使用转录组分析来探究肌病致病基因（即那些突变会导致骨骼肌发病的基因）的表达动态。结果显示，45%的肌病致病基因在卫星细胞早期激活阶段（0 - 5小时）存在差异表达。在这271个肌病致病基因中，有83个对卫星细胞的主要调节因子Pax7有反应。我们的分析表明，在所有类别的许多神经肌肉疾病中，包括那些骨骼肌病理特征不突出的疾病，卫星细胞功能可能都受到了干扰。这一特征描述有助于进一步理解发病机制，并为预后和诊断工具的开发提供信息，最终推动新疗法的研发。
