Duchenne muscular dystrophy (DMD) is an X-linked disease caused by null mutations in dystrophin and characterized by muscle degeneration. Cardiomyopathy is common and often prevalent at similar frequency in female DMD carriers irrespective of whether they manifest skeletal muscle disease. Impaired muscle nitric oxide (NO) production in DMD disrupts muscle blood flow regulation and exaggerates post-exercise fatigue. We show that circulating levels of endogenous methylated arginines including asymmetric dimethylarginine (ADMA), which act as NO synthase inhibitors, are elevated by acute necrotic muscle damage and in chronically-necrotic dystrophin-deficient mice. We therefore hypothesized that excessive ADMA impairs muscle NO production and diminishes exercise tolerance in DMD. We used transgenic expression of dimethylarginine dimethylaminohydrolase 1 (DDAH), which degrades methylated arginines, to investigate their contribution to exercise-induced fatigue in DMD. Although infusion of exogenous ADMA was sufficient to impair exercise performance in wild-type mice, transgenic DDAH expression did not rescue exercise-induced fatigue in dystrophin-deficient male mdx mice. Surprisingly, DDAH transgene expression did attenuate exercise-induced fatigue in dystrophin-heterozygous female mdx carrier mice. Improved exercise tolerance was associated with reduced heart weight and improved cardiac β-adrenergic responsiveness in DDAH-transgenic mdx carriers. We conclude that DDAH overexpression increases exercise tolerance in female DMD carriers, possibly by limiting cardiac pathology and preserving the heart's responses to changes in physiological demand. Methylated arginine metabolism may be a new target to improve exercise tolerance and cardiac function in DMD carriers, or act as an adjuvant to promote NO signaling alongside therapies that partially restore dystrophin expression in DMD patients.

中文翻译：

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增强的二甲基精氨酸降解可改善 Duchenne 肌营养不良症携带小鼠的冠状动脉血流储备和运动耐量。

杜氏肌营养不良症 (DMD) 是一种 X 连锁疾病，由肌营养不良蛋白的无效突变引起，以肌肉退化为特征。心肌病在女性 DMD 携带者中很常见，并且通常以相似的频率流行，无论她们是否表现出骨骼肌疾病。DMD 中肌肉一氧化氮 (NO) 生成受损会破坏肌肉血流调节并加剧运动后疲劳。我们表明，在急性坏死性肌肉损伤和慢性坏死性肌营养不良蛋白缺陷小鼠中，内源性甲基化精氨酸（包括作为 NO 合酶抑制剂的不对称二甲基精氨酸 (ADMA)）的循环水平升高。因此，我们假设过量的 ADMA 会损害肌肉 NO 的产生并降低 DMD 的运动耐量。我们使用降解甲基化精氨酸的二甲基精氨酸二甲基氨基水解酶 1 (DDAH) 的转基因表达来研究它们对 DMD 运动引起的疲劳的贡献。虽然输注外源性 ADMA 足以损害野生型小鼠的运动表现，但转基因 DDAH 表达并不能挽救抗肌萎缩蛋白缺陷雄性 mdx 小鼠运动引起的疲劳。令人惊讶的是，DDAH 转基因表达确实减轻了肌营养不良蛋白杂合雌性 mdx 携带小鼠的运动引起的疲劳。在 DDAH 转基因 mdx 携带者中，运动耐量的提高与心脏重量的减轻和心脏 β-肾上腺素能反应的改善有关。我们得出结论，DDAH 过度表达增加了女性 DMD 携带者的运动耐量，可能是通过限制心脏病理学和保护心脏。对生理需求变化的反应。甲基化精氨酸代谢可能是改善 DMD 携带者运动耐量和心脏功能的新目标，或作为促进 NO 信号传导的辅助剂，以及部分恢复 DMD 患者肌营养不良蛋白表达的疗法。