de Souza Leite Felipe, Lambert Matthias R, Zhang Tracy Yuanfan, Conner James R, Paulo Joao A, Oliveira Sheldon Furtado, Thakurta Sanjukta, Bowles Jennifer, Gussoni Emanuela, Gygi Steven P, Widrick Jeffrey J, Kunkel Louis M
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics and Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
bioRxiv. 2025 Mar 14:2025.03.12.642857. doi: 10.1101/2025.03.12.642857.
Therapeutic strategies for Duchenne Muscular Dystrophy (DMD) will likely require complementary approaches. One possibility is to explore genetic modifiers that improve muscle regeneration and function. The beneficial effects of the overexpression of Jagged-1 were described in escaper golden retriever muscular dystrophy (GRMD) dogs that had a near-normal life and validated in dystrophin-deficient zebrafish (1). To clarify the underlying biology of overexpression in dystrophic muscles, we generated a transgenic mouse (mdx-) model that lacks dystrophin and overexpresses human in striated muscles. Skeletal muscles from mdx- and mdx mice were studied at one, four, and twelve-month time points. expression in mdx- increased by three to five times compared to mdx. Consequently, mdx- muscles were significantly bigger and stronger than dystrophic controls, along with an increased number of myofibers. Proteomics data show increased dysferlin in mdx- muscles and an association of Nsd1 with the phenotype. Our data supports the positive effect of overexpression in dystrophic muscles.
杜氏肌营养不良症（DMD）的治疗策略可能需要采用互补方法。一种可能性是探索能够改善肌肉再生和功能的基因修饰因子。在具有近乎正常生活的逃脱型金毛寻回犬型肌营养不良症（GRMD）犬中描述了Jagged-1过表达的有益效果，并在缺乏肌营养不良蛋白的斑马鱼中得到验证（1）。为了阐明营养不良肌肉中过表达的潜在生物学机制，我们构建了一种转基因小鼠（mdx-）模型，该模型缺乏肌营养不良蛋白并在横纹肌中过表达人[此处原文似乎缺失某个基因名称]。在1个月、4个月和12个月的时间点对mdx-和mdx小鼠的骨骼肌进行了研究。与mdx相比，mdx-中[此处原文似乎缺失某个基因名称]的表达增加了三到五倍。因此，mdx-肌肉明显比营养不良对照组更大更强壮，同时肌纤维数量增加。蛋白质组学数据显示mdx-肌肉中dysferlin增加，并且Nsd1与该表型相关。我们的数据支持[此处原文似乎缺失某个基因名称]过表达在营养不良肌肉中的积极作用。
