Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to decrease the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs). Using a metabolomics-based approach, we observed distinct and transient molecular phenotypes in muscles of dystrophin-deficient MDX mice subjected to ECCs. Among the most chronically depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit using two complementary small molecule strategies: provision of a biosynthetic precursor, nicotinamide riboside, or specific inhibition of the NAD-degrading ADP-ribosyl cyclase, CD38. Administering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, with a pronounced impact on intermediates of the pentose phosphate pathway, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy sustainably increased the bulk tissue NAD pool, lessened muscle damage markers, nor improved maximal hindlimb strength following repeated rounds of eccentric challenge and recovery. In the absence of dystrophin, eccentric injury contributes to chronic intramuscular NAD depletion with broad pleiotropic effects on the molecular phenotype of the tissue. These molecular consequences can be more effectively overcome by inhibiting the enzymatic activity of CD38 than by supplementing nicotinamide riboside. However, we found no evidence that either small molecule strategy is sufficient to restore muscle contractile function or confer protection from eccentric injury, undermining the modulation of NAD metabolism as a therapeutic approach for DMD.

中文翻译：

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补充 NAD+ 替代策略无法在功能上保护肌营养不良蛋白缺乏的肌肉


杜氏肌营养不良症 (DMD) 是一种由于功能性肌营养不良蛋白缺失而导致的进行性肌肉萎缩性疾病。目前 DMD 的治疗选择有限，因为小分子疗法在很大程度上仍然无法降低偏心收缩 (ECC) 期间肌肉重复机械损伤的发生率或减轻其后果。使用基于代谢组学的方法，我们观察到接受 ECC 的肌营养不良蛋白缺陷 MDX 小鼠肌肉中独特且短暂的分子表型。长期消耗最多的代谢物是烟酰胺腺嘌呤二核苷酸（NAD），它是一种重要的代谢辅助因子，可以保护肌肉免受随着时间的推移而发生结构和代谢退化。我们测试了是否可以使用两种互补的小分子策略来扩展 MDX 肌肉 NAD 池以获得治疗益处：提供生物合成前体烟酰胺核苷，或特异性抑制 NAD 降解 ADP-核糖基环化酶 CD38。给 MDX 小鼠施用一种新型、有效、口服的 CD38 拮抗剂，成功地将大部分肌肉代谢组恢复到野生型状态，对戊糖磷酸途径的中间体产生显着影响，而补充烟酰胺核苷并没有显着影响分子表型肌肉的。然而，这两种策略都没有可持续地增加大量组织 NAD 池、减少肌肉损伤标记物，也没有提高重复几轮离心挑战和恢复后的最大后肢力量。在缺乏肌营养不良蛋白的情况下，偏心损伤会导致慢性肌内 NAD 消耗，对组织的分子表型具有广泛的多效性作用。 通过抑制 CD38 的酶活性比补充烟酰胺核苷可以更有效地克服这些分子后果。然而，我们没有发现任何证据表明小分子策略足以恢复肌肉收缩功能或提供对偏心损伤的保护，从而破坏 NAD 代谢的调节作为 DMD 的治疗方法。