Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
Department of Pediatrics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
Acta Neuropathol Commun. 2018 Nov 7;6(1):119. doi: 10.1186/s40478-018-0620-3.
Pompe disease is a metabolic myopathy that is caused by glycogen accumulation as a result of deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Previously, we showed that adult muscle stem cells termed satellite cells are present at normal levels in muscle from patients with Pompe disease, but that these are insufficiently activated to repair the severe muscle pathology. Here we characterized the muscle regenerative response during disease progression in a mouse model of Pompe disease and investigated the intrinsic capacity of Gaa satellite cells to regenerate muscle damage. Gaa mice showed progressive muscle pathology from 15 weeks of age as reflected by increased lysosomal size, decreased fiber diameter and reduced muscle wet weight. Only during the first 15 weeks of life but not thereafter, we detected a gradual increase in centrally nucleated fibers and proliferating satellite cells in Gaa muscle, indicating a mild regenerative response. The levels of Pax7-positive satellite cells were increased in Gaa mice at all ages, most likely as result of enhanced satellite cell activation in young Gaa animals. Surprisingly, both young and old Gaa mice regenerated experimentally-induced muscle injury efficiently as judged by rapid satellite cell activation and complete restoration of muscle histology. In response to serial injury, Gaa mice also regenerated muscle efficiently and maintained the satellite cell pool. These findings suggest that, similar to human patients, Gaa mice have insufficient satellite cell activation and muscle regeneration during disease progression. The initial endogenous satellite cell response in Gaa mice may contribute to the delayed onset of muscle wasting compared to human patients. The rapid and efficient regeneration after experimental muscle injury suggest that Gaa satellite cells are functional stem cells, opening avenues for developing muscle regenerative therapies for Pompe disease.
庞贝病是一种代谢性肌病，由于溶酶体酶酸性α-葡萄糖苷酶（GAA）缺乏，导致糖原积累。此前，我们发现，在庞贝病患者的肌肉中，正常水平存在一种称为卫星细胞的成体肌肉干细胞，但这些细胞激活不足，无法修复严重的肌肉病变。在这里，我们在庞贝病的小鼠模型中描述了疾病进展过程中的肌肉再生反应，并研究了 Gaa 卫星细胞修复肌肉损伤的内在能力。Gaa 小鼠从 15 周龄开始出现进行性肌肉病变，表现为溶酶体增大、纤维直径减小和肌肉湿重降低。只有在生命的前 15 周，而不是之后，我们才在 Gaa 肌肉中检测到中央核纤维和增殖卫星细胞的逐渐增加，表明存在轻度的再生反应。在所有年龄段，Gaa 小鼠中的 Pax7 阳性卫星细胞水平都增加了，这很可能是由于年轻 Gaa 动物中卫星细胞激活增强所致。令人惊讶的是，无论是年轻还是年老的 Gaa 小鼠，在实验性肌肉损伤后都能有效地进行卫星细胞激活，并完全恢复肌肉组织学，这表明它们具有高效的再生能力。在对连续损伤的反应中，Gaa 小鼠也能有效地再生肌肉并维持卫星细胞池。这些发现表明，与人类患者相似，Gaa 小鼠在疾病进展过程中卫星细胞激活和肌肉再生不足。Gaa 小鼠中初始的内源性卫星细胞反应可能有助于延迟与人类患者相比的肌肉消耗的发生。实验性肌肉损伤后的快速和有效的再生表明，Gaa 卫星细胞是功能性干细胞，为开发庞贝病的肌肉再生疗法开辟了途径。
