Deparment of Biochemistry and Molecular Biology, Saint Louis University, Doisy Research #4171100 South Grand, Saint Louis, MO, 63104, USA.
Sci Rep. 2024 Nov 2;14(1):26437. doi: 10.1038/s41598-024-77911-8.
Facioscapulohumeral muscular dystrophy (FSHD) is a degenerative muscle disease caused by loss of epigenetic silencing and ectopic reactivation of the embryonic double homeobox protein 4 gene (DUX4) in skeletal muscle. The p38 MAP kinase inhibitor losmapimod is currently being tested in FSHD clinical trials due to the finding that p38 inhibition suppresses DUX4 expression in preclinical models. However, the role of p38 in regulating DUX4 at different myogenic stages has not been investigated. We used genetic and pharmacologic tools in FSHD patient-derived myoblasts/myocytes to explore the temporal role of p38 in differentiation-induced DUX4 expression. Deletion of MAPK14/11 or inhibition of p38α/β caused a significant reduction in early differentiation-dependent increases in DUX4 and DUX4 target gene expression. However, in MAPK14/11 knockout cells, there remains a differentiation-associated increase in DUX4 and DUX4 target gene expression later in differentiation. Furthermore, pharmacologic inhibition of p38α/β only partially decreased DUX4 and DUX4 target gene expression in late differentiating myotubes. In xenograft studies, p38α/β inhibition by losmapimod failed to suppress DUX4 target gene expression in late FSHD xenografts. Our results show that while p38 is critical for DUX4 expression during early myogenesis, later in myogenesis a significant level of DUX4 expression is independent of p38α/β activity.
面肩肱型肌营养不良症（FSHD）是一种退行性肌肉疾病，由胚胎双同源盒蛋白 4 基因（DUX4）在骨骼肌中的表观遗传沉默丧失和异位重新激活引起。由于发现 p38 抑制可在临床前模型中抑制 DUX4 的表达，因此目前正在 FSHD 临床试验中测试 p38 MAP 激酶抑制剂 losmapimod。然而，p38 在调节不同的成肌阶段的 DUX4 方面的作用尚未得到研究。我们使用 FSHD 患者来源的成肌细胞/肌细胞中的遗传和药理学工具，探索 p38 在分化诱导的 DUX4 表达中的时间作用。MAPK14/11 的缺失或 p38α/β 的抑制导致早期分化依赖性 DUX4 和 DUX4 靶基因表达的显著减少。然而，在 MAPK14/11 敲除细胞中，在分化后期仍然存在与分化相关的 DUX4 和 DUX4 靶基因表达增加。此外，p38α/β 的药理学抑制仅部分降低了晚期分化肌管中的 DUX4 和 DUX4 靶基因表达。在异种移植研究中，losmapimod 抑制 p38α/β 未能抑制晚期 FSHD 异种移植物中的 DUX4 靶基因表达。我们的结果表明，虽然 p38 在早期成肌过程中对 DUX4 表达至关重要，但在成肌后期，相当水平的 DUX4 表达独立于 p38α/β 活性。
