Complementary NAD(+) replacement strategies fail to functionally protect dystrophin-deficient muscle.
Complementary NAD(+) replacement strategies fail to functionally protect dystrophin-deficient muscle.
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DOI：
10.1186/s13395-020-00249-y
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发表时间：
2020-10-22
期刊：
影响因子：
4.9
通讯作者：
Kramer HF
中科院分区：
文献类型：
--
作者：
Frederick DW;McDougal AV;Semenas M;Vappiani J;Nuzzo A;Ulrich JC;Becherer JD;Preugschat F;Stewart EL;Sévin DC;Kramer HF
杜氏肌营养不良症（DMD）是一种由功能性肌营养不良蛋白丧失引起的进行性肌肉萎缩症。目前DMD的治疗选择是有限的，因为小分子模式在很大程度上仍然无法降低发生率或减轻偏心收缩（ECCs）期间对肌肉的重复性机械损伤的后果。使用基于代谢组学的方法，我们观察到ECCs作用下肌营养不良蛋白缺陷MDX小鼠肌肉中不同的瞬时分子表型。长期消耗最多的代谢物是烟酰胺腺嘌呤二核苷酸（NAD），这是一种必要的代谢辅助因子，可以保护肌肉免受结构和代谢退化的影响。我们测试了MDX肌肉NAD库是否可以通过两种互补的小分子策略来扩大治疗效益：提供生物合成前体，烟酰胺核苷，或特异性抑制nadd降解adp -核糖基环化酶CD38。给MDX小鼠一种新型的、有效的、可口服的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产物有显著影响，而补充烟酰胺核苷对肌肉的分子表型没有显著影响。然而，这两种策略都不能持续地增加大块组织NAD池，减少肌肉损伤标记，也不能在反复的偏心挑战和恢复后提高最大后肢力量。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耗损，并对组织的分子表型产生广泛的多向性影响。这些分子后果可以通过抑制CD38的酶活性比补充烟酰胺核苷更有效地克服。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保护免受偏心损伤，从而破坏了NAD代谢的调节作为DMD的治疗方法。
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.
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影响因子：
29
作者：
Frederick DW;Loro E;Liu L;Davila A Jr;Chellappa K;Silverman IM;Quinn WJ 3rd;Gosai SJ;Tichy ED;Davis JG;Mourkioti F;Gregory BD;Dellinger RW;Redpath P;Migaud ME;Nakamaru-Ogiso E;Rabinowitz JD;Khurana TS;Baur JA
通讯作者：
Baur JA
影响因子：
7.3
作者：
Becherer, J. David;Boros, Eric E.;Ulrich, John C.
通讯作者：
Ulrich, John C.
影响因子：
7.4
作者：
Fuhrer, Tobias;Heer, Dominik;Zamboni, Nicola
通讯作者：
Zamboni, Nicola
影响因子：
7.1
作者：
Dollerup, Ole L.;Christensen, Britt;Jessen, Niels
通讯作者：
Jessen, Niels
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y