Chen Kenric, Wei Erdong, Mitanoska Ana, Gearhart Micah D, Kyba Michael, Bosnakovski Darko
Department of Pediatrics and Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN 55455, USA.
Cells. 2025 May 12;14(10):695. doi: 10.3390/cells14100695.
Double homeobox (DUX) genes are key embryonic regulators that are silenced after the early cleavage stages of embryogenesis. Aberrant expression of DUX4 in skeletal muscle is linked to facioscapulohumeral muscular dystrophy (FSHD). A recent study reported that Dux, the murine ortholog of DUX4, contributes to the dystrophic phenotype in mdx mice, a Duchenne muscular dystrophy (DMD) model, and that its deletion enhances muscle regeneration by reducing oxidative stress. However, convincing evidence of Dux expression in either intact or injured muscle of wild-type (WT) and mdx mice remains lacking, raising questions about its role in muscle homeostasis. To investigate this, we assessed Dux expression in WT and mdx mice and used knockout (Dux) mice to evaluate its function during regeneration following cardiotoxin (CTX)-induced injury. Contrary to prior reports, Dux was not expressed in either WT or mdx mice. Moreover, Dux deletion did not enhance muscle regeneration or affect the expression of the oxidative stress regulator Nrf2 following CTX injury. Lastly, we confirmed that neither DUX4 nor its target genes were induced in muscle biopsies from DMD patients, excluding a role for DUX4 in DMD pathology. Collectively, our results demonstrate that Dux does not impact skeletal muscle regeneration or DUX4 contribution to the DMD dystrophic phenotype, directly challenging the conclusions of a previously published study. We comment on issues of editorial oversight that led to the publication of that study and highlight the deleterious impact of the growing wave of fraudulent publications.
双同源盒（DUX）基因是关键的胚胎调节因子，在胚胎发育的早期卵裂阶段后会被沉默。DUX4在骨骼肌中的异常表达与面肩肱型肌营养不良症（FSHD）有关。最近的一项研究报告称，DUX4的小鼠直系同源基因Dux促成了杜氏肌营养不良症（DMD）模型mdx小鼠的营养不良表型，并且其缺失通过降低氧化应激来增强肌肉再生。然而，野生型（WT）和mdx小鼠完整或受损肌肉中Dux表达的令人信服的证据仍然缺乏，这引发了关于其在肌肉稳态中作用的疑问。为了研究这一点，我们评估了WT和mdx小鼠中Dux的表达，并使用基因敲除（Dux）小鼠来评估其在心脏毒素（CTX）诱导损伤后的再生过程中的功能。与先前的报道相反，Dux在WT或mdx小鼠中均未表达。此外，Dux缺失并未增强肌肉再生，也未影响CTX损伤后氧化应激调节因子Nrf2的表达。最后，我们证实DMD患者的肌肉活检中既未诱导DUX4也未诱导其靶基因，排除了DUX4在DMD病理学中的作用。总体而言，我们的结果表明Dux不会影响骨骼肌再生或DUX4对DMD营养不良表型的影响，直接挑战了先前发表的一项研究的结论。我们对导致该研究发表的编辑监督问题进行了评论，并强调了日益增多的欺诈性出版物浪潮的有害影响。
