Lillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USA.
Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
Int J Mol Sci. 2022 Feb 11;23(4):1983. doi: 10.3390/ijms23041983.
FSHD is caused by loss of silencing of the DUX4 gene, but the DUX4 protein has not yet been directly detected immunohistologically in affected muscle, raising the possibility that DUX4 expression may occur at time points prior to obtaining adult biopsies for analysis, with consequent perturbations of muscle being responsible for disease progression. To test the extent to which muscle can regenerate following DUX4-mediated degeneration, we employed an animal model with reversible DUX4 expression, the iDUX4pA;HSA mouse. We find that muscle histology does recover substantially after DUX4 expression is switched off, with the extent of recovery correlating inversely with the duration of prior DUX4 expression. However, despite fairly normal muscle histology, and recovery of most cytological parameters, the fibroadipogenic progenitor compartment, which is significantly elevated during bouts of fiber-specific DUX4 expression, does not return to basal levels, even many weeks after a single burst of DUX4 expression. We find that muscle that has recovered from a DUX4 burst acquires a propensity for severe fibrosis, which can be revealed by subsequent cardiotoxin injuries. These results suggest that a past history of DUX4 expression leads to maintained pro-fibrotic alterations in the cellular physiology of muscle, with potential implications for therapeutic approaches.
FSHD 是由 DUX4 基因沉默丧失引起的，但在受影响的肌肉中尚未直接通过免疫组织化学检测到 DUX4 蛋白，这使得 DUX4 表达可能发生在获得用于分析的成人活检之前的时间点，随后肌肉的紊乱导致疾病进展。为了测试 DUX4 介导的退化后肌肉可以在多大程度上再生，我们使用了一种具有可逆 DUX4 表达的动物模型，即 iDUX4pA；HSA 小鼠。我们发现，在关闭 DUX4 表达后，肌肉组织学确实有了很大的恢复，恢复的程度与之前 DUX4 表达的持续时间成反比。然而，尽管肌肉组织学相当正常，大多数细胞学参数也得到了恢复，但纤维特异性 DUX4 表达期间显著升高的纤维脂肪祖细胞区室并没有恢复到基础水平，即使在 DUX4 表达的单次爆发后数周也是如此。我们发现，从 DUX4 爆发中恢复的肌肉会产生严重纤维化的倾向，这可以通过随后的心脏毒素损伤来揭示。这些结果表明，过去的 DUX4 表达会导致肌肉细胞生理的持续促纤维化改变，这可能对治疗方法有潜在影响。
