Timpani Cara A, Mamchaoui Kamel, Butler-Browne Gillian, Rybalka Emma
Institute for Health and Sport, Victoria University, Melbourne 8001, Victoria, Australia.
Australian Institute for Musculoskeletal Science, St Albans 3021, Victoria, Australia.
Antioxidants (Basel). 2020 Dec 13;9(12):1268. doi: 10.3390/antiox9121268.
The discordance between pre-clinical success and clinical failure of treatment options for Duchenne Muscular Dystrophy (DMD) is significant. The termination of clinical trials investigating the phosphodiesterase inhibitors, sildenafil and tadalafil (which prolong the second messenger molecule of nitric oxide (NO) signaling), are prime examples of this. Both attenuated key dystrophic features in the mouse model of DMD yet failed to modulate primary outcomes in clinical settings. We have previously attempted to modulate NO signaling via chronic nitrate supplementation of the mouse but failed to demonstrate beneficial modulation of key dystrophic features (i.e., metabolism). Instead, we observed increased muscle damage and nitrosative stress which exacerbated MD. Here, we highlight that acute nitrite treatment of human DMD myoblasts is also detrimental and suggest strategies for moving forward with NO replacement therapy in DMD.
杜氏肌营养不良症（DMD）治疗方案在临床前研究取得成功但在临床试验中失败的情况极为显著。针对磷酸二酯酶抑制剂西地那非和他达拉非（可延长一氧化氮（NO）信号的第二信使分子）开展的临床试验终止，就是这方面的典型例子。这两种药物在DMD小鼠模型中均减轻了关键的营养不良特征，但在临床环境中未能调节主要结局。我们之前曾尝试通过长期给小鼠补充硝酸盐来调节NO信号，但未能证明对关键的营养不良特征（即代谢）有有益调节作用。相反，我们观察到肌肉损伤和亚硝化应激增加，这加剧了肌营养不良症。在此，我们强调对人DMD成肌细胞进行急性亚硝酸盐处理也是有害的，并提出了在DMD中推进NO替代疗法的策略。
