Gibson Aaron M, Pan Xiufang, Brito-Estrada Omar, Teixeira James A, Carl Lauren K, Yue Yongping, Kamradt Michael L, Burke Matthew J, Wadding-Lee Caris A, Yao Gang, Herzog Roland W, Duan Dongsheng, Makarewich Catherine A
The Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA.
Dis Model Mech. 2025 Jun 1;18(6). doi: 10.1242/dmm.052285. Epub 2025 Jun 25.
Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease driven by cytosolic calcium overload, which leads to muscle degeneration. Sarco/endoplasmic reticulum calcium ATPase (SERCA), a key regulator of cytosolic calcium levels, exhibits reduced activity in animal models of DMD and human patients. Dwarf open reading frame (DWORF), a positive SERCA regulator, is downregulated in mdx DMD mice, and adeno-associated virus-mediated DWORF overexpression has been shown to ameliorate DMD cardiomyopathy. The canine DMD model provides a crucial bridge for translating findings from mice to humans. To investigate DWORF expression in this model, we developed a canine-specific anti-DWORF antibody, as the existing murine antibody is ineffective. This antibody detected DWORF in human, pig, cat and rabbit muscle, but not in mouse muscle. DWORF was absent in muscle tissues of neonatal normal dogs but highly expressed in those of adult dogs. In DMD-affected dogs aged 8 months or older, DWORF expression was significantly reduced in both cardiac and skeletal muscle. This study establishes a foundation for evaluating DWORF-based gene therapy in the canine DMD model, advancing the potential for clinical translation.
杜兴氏肌营养不良症（DMD）是一种由胞质钙超载驱动的致死性肌肉萎缩疾病，可导致肌肉退化。肌浆网/内质网钙ATP酶（SERCA）是胞质钙水平的关键调节因子，在DMD动物模型和人类患者中活性降低。矮小开放阅读框（DWORF）是一种SERCA正向调节因子，在mdx DMD小鼠中表达下调，腺相关病毒介导的DWORF过表达已被证明可改善DMD心肌病。犬类DMD模型为将小鼠研究结果转化为人类研究结果提供了关键桥梁。为了研究该模型中DWORF的表达情况，我们开发了一种犬特异性抗DWORF抗体，因为现有的鼠源抗体无效。该抗体在人类、猪、猫和兔的肌肉中检测到了DWORF，但在小鼠肌肉中未检测到。新生正常犬的肌肉组织中不存在DWORF，但在成年犬的肌肉组织中高表达。在8个月及以上受DMD影响的犬中，心脏和骨骼肌中的DWORF表达均显著降低。本研究为在犬类DMD模型中评估基于DWORF的基因治疗奠定了基础，推动了临床转化的可能性。
