Fulcrum Therapeutics, Cambridge, Massachusetts (L.A.R., E.V., A.A., J.M., N.S., A.R., S.K., P.R., D.C., L.A.T., L.R., A.N.C., A.M.C., O.W.) and University of Rochester Medical Center, Department of Neurology, Rochester, New York (R.T.)
Fulcrum Therapeutics, Cambridge, Massachusetts (L.A.R., E.V., A.A., J.M., N.S., A.R., S.K., P.R., D.C., L.A.T., L.R., A.N.C., A.M.C., O.W.) and University of Rochester Medical Center, Department of Neurology, Rochester, New York (R.T.).
J Pharmacol Exp Ther. 2020 Sep;374(3):489-498. doi: 10.1124/jpet.119.264689. Epub 2020 Jun 23.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of repression at the locus leading to aberrant double homeobox 4 (DUX4) expression in skeletal muscle. Activation of this early embryonic transcription factor results in the expression of its target genes causing muscle fiber death. Although progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38 as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent, and specific inhibitors of p38/, we show a robust reduction of DUX4 expression, activity, and cell death across patient-derived FSHD1 and FSHD2 lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38/ inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38/ inhibitors as effective therapeutics to treat FSHD at its root cause. SIGNIFICANCE STATEMENT: Using patient-derived facioscapulohumeral muscular dystrophy (FSHD) myotubes, we characterize the pharmacological relationships between p38/ inhibition, double homeobox 4 (DUX4) expression, its downstream transcriptional program, and muscle cell death. p38/ inhibition results in potent and specific DUX4 downregulation across multiple genotypes without significant effects in the process of myogenesis in vitro. These findings highlight the potential of p38/ inhibitors for the treatment of FSHD, a condition that today has no approved therapies.
面肩肱型肌营养不良症（FSHD）是由于在 基因座失去抑制，导致骨骼肌中异常双同源盒 4（DUX4）表达引起的。这种早期胚胎转录因子的激活导致其靶基因的表达，从而导致肌肉纤维死亡。尽管在理解驱动 DUX4 表达的信号方面已经取得了进展，但该基因的转录激活所涉及的因素和途径在很大程度上仍不清楚。在这里，我们描述了 p38 作为 FSHD 肌管中 DUX4 表达的新型调节剂的鉴定和特征。通过使用多种高度表征、有效和特异性的 p38/抑制剂，我们在源自 FSHD1 和 FSHD2 患者的细胞系中显示出 DUX4 表达、活性和细胞死亡的显著减少。RNA-seq 分析揭示了在 p38/抑制后少数基因的差异表达，其中绝大多数是 DUX4 的靶基因。我们的结果揭示了 p38α 在 FSHD 中 DUX4 异常激活中的新的、显然至关重要的作用，并支持 p38/抑制剂作为治疗 FSHD 的有效疗法，从根本上治疗该疾病。
使用源自面肩肱型肌营养不良症（FSHD）的肌管，我们描述了 p38/抑制、双同源盒 4（DUX4）表达、其下游转录程序以及肌肉细胞死亡之间的药理关系。p38/抑制导致多种基因型的 DUX4 表达强烈而特异性地下调，而对体外肌发生过程没有显著影响。这些发现突出了 p38/抑制剂在治疗 FSHD 方面的潜力，目前尚无批准的治疗方法。
