Univ Paris Est Creteil, INSERM, IMRB, 94010, Creteil, France.
Centre of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Acta Neuropathol Commun. 2023 Oct 19;11(1):167. doi: 10.1186/s40478-023-01657-z.
Duchenne muscular dystrophy (DMD) is a devastating X-linked muscular disease, caused by mutations in the DMD gene encoding Dystrophin and affecting 1:5000 boys worldwide. Lack of Dystrophin leads to progressive muscle wasting and degeneration resulting in cardiorespiratory failure. Despite the absence of a definitive cure, innovative therapeutic avenues are emerging. Myopathologic studies are important to further understand the biological mechanisms of the disease and to identify histopathologic benchmarks for clinical evaluations. We conducted a myopathologic analysis on twenty-four muscle biopsies from DMD patients, with particular emphasis on regeneration, fibro-adipogenic progenitors and muscle stem cells behavior. We describe an increase in content of fibro-adipogenic progenitors, central orchestrators of fibrotic progression and lipid deposition, concurrently with a decline in muscle regenerative capacity. This regenerative impairment strongly correlates with compromised activation and expansion of muscle stem cells. Furthermore, our study uncovers an early acquisition of a senescence phenotype by DMD-afflicted muscle stem cells. Here we describe the myopathologic trajectory intrinsic to DMD and establish muscle stem cell senescence as a pivotal readout for future therapeutic interventions.
杜氏肌营养不良症（DMD）是一种破坏性的 X 连锁肌肉疾病，由编码肌营养不良蛋白的 DMD 基因突变引起，影响全球每 5000 名男孩中的 1 名。缺乏肌营养不良蛋白会导致肌肉进行性消瘦和退化，从而导致心肺衰竭。尽管没有明确的治愈方法，但新的治疗途径正在出现。肌病理研究对于进一步了解疾病的生物学机制以及确定临床评估的组织病理学基准非常重要。我们对 24 例 DMD 患者的肌肉活检进行了肌病理分析，特别强调了再生、纤维脂肪祖细胞和肌肉干细胞行为。我们描述了纤维脂肪祖细胞含量的增加，纤维发生进展和脂质沉积的中枢协调者，同时肌肉再生能力下降。这种再生损伤与肌肉干细胞激活和扩增受损强烈相关。此外，我们的研究揭示了 DMD 受累肌肉干细胞早期获得衰老表型。在这里，我们描述了 DMD 内在的肌病理轨迹，并确立了肌肉干细胞衰老作为未来治疗干预的关键指标。
