Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model.
Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model.
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DOI：
10.1073/pnas.2018342118
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发表时间：
2021-03-02
影响因子：
11.1
通讯作者：
Szewczyk NJ
中科院分区：
文献类型：
--
作者：
Ellwood RA;Hewitt JE;Torregrossa R;Philp AM;Hardee JP;Hughes S;van de Klashorst D;Gharahdaghi N;Anupom T;Slade L;Deane CS;Cooke M;Etheridge T;Piasecki M;Antebi A;Lynch GS;Philp A;Vanapalli SA;Whiteman M;Szewczyk NJ
杜氏肌营养不良症（DMD）是一种无法治愈的致命性退行性疾病。目前的标准药物治疗是皮质类固醇。它们的长期使用与几种不良副作用有关。使用秀丽隐杆线虫，我们已经确定了补充硫化氢（H2S）的药物治疗。一种是钠GYY 4137，主要像泼尼松一样改善神经肌肉健康;另一种是AP 39，靶向将H2S输送到线粒体。由于这些不是类固醇，它们不太可能产生类固醇诱导的副作用。此外，由于DMD小鼠显示出总硫化物的下降，我们的结果为评估DMD病理学中的细胞和/或线粒体H2S铺平了道路，并保证进一步研究在mdx小鼠和/或DMD高等动物模型中选择性H2S递送方法。杜氏肌营养不良症（DMD）是一种X连锁隐性疾病，其特征是由于肌营养不良蛋白基因突变导致的进行性肌肉变性和无力。DMD的症状与加速老化的症状相似。最近，硫化氢（H2S）补充剂已被建议调节与年龄相关的肌肉功能下降的影响，代谢H2S缺乏症已被牵连在影响肌肉质量的条件，如苯丙酮尿症。因此，我们评估了使用钠GYY 4137（NaGYY），一种H2S释放分子，作为DMD治疗的可能方法。使用dys-1（eg 33）秀丽隐杆线虫DMD模型，我们发现NaGYY治疗（100 µM）改善了运动，力量，步态和肌肉线粒体结构，与金标准治疗方法泼尼松（370 µM）相似。任何一种治疗的健康改善都需要激酶JNK-1、转录因子SKN-1和NAD依赖性脱乙酰酶SIR-2.1的作用。NaGYY治疗的健康益处需要转录因子β-16，而不是泼尼松治疗。AP 39（100 pM）是一种靶向H2S的化合物，也改善了dys-1（eg 33）模型的运动和力量，进一步表明这些改善是基于H2S的。此外，我们发现在抗肌萎缩蛋白/utrophin基因敲除小鼠中总硫化物和H2S产生酶下降。总体而言，我们的结果表明，H2S缺陷可能有助于DMD病理，并且用H2S递送化合物矫正/克服缺陷具有作为DMD治疗的治疗方法的潜力。
Duchenne muscular dystrophy (DMD) is a fatal degenerative disease without a cure. Current standard pharmacological treatment is corticosteroids. Their prolonged use is associated with several undesirable side effects. Using Caenorhabditis elegans, we have identified pharmacological treatments that supplement hydrogen sulfide (H2S). One, sodium GYY4137, largely acts like prednisone to improve neuromuscular health; the other, AP39, targets H2S delivery to mitochondria. As these are not steroids, they are unlikely to produce steroid-induced side effects. Additionally, as DMD mice show a decline in total sulfide, our results pave the way for evaluation of cellular and/or mitochondrial H2S in DMD pathology and warrant further investigation of selective H2S delivery approaches in mdx mice and/or higher animal models of DMD. Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle degeneration and weakness due to mutations in the dystrophin gene. The symptoms of DMD share similarities with those of accelerated aging. Recently, hydrogen sulfide (H2S) supplementation has been suggested to modulate the effects of age-related decline in muscle function, and metabolic H2S deficiencies have been implicated in affecting muscle mass in conditions such as phenylketonuria. We therefore evaluated the use of sodium GYY4137 (NaGYY), a H2S-releasing molecule, as a possible approach for DMD treatment. Using the dys-1(eg33) Caenorhabditis elegans DMD model, we found that NaGYY treatment (100 µM) improved movement, strength, gait, and muscle mitochondrial structure, similar to the gold-standard therapeutic treatment, prednisone (370 µM). The health improvements of either treatment required the action of the kinase JNK-1, the transcription factor SKN-1, and the NAD-dependent deacetylase SIR-2.1. The transcription factor DAF-16 was required for the health benefits of NaGYY treatment, but not prednisone treatment. AP39 (100 pM), a mitochondria-targeted H2S compound, also improved movement and strength in the dys-1(eg33) model, further implying that these improvements are mitochondria-based. Additionally, we found a decline in total sulfide and H2S-producing enzymes in dystrophin/utrophin knockout mice. Overall, our results suggest that H2S deficit may contribute to DMD pathology, and rectifying/overcoming the deficit with H2S delivery compounds has potential as a therapeutic approach to DMD treatment.
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影响因子：
3.7
作者：
Baron, Daniel;Magot, Armelle;Pereon, Yann
通讯作者：
Pereon, Yann
影响因子：
2.2
作者：
Bessou, C;Giugia, JB;Ségalat, L
通讯作者：
Ségalat, L
DOI：
10.4103/0019-5278.34529
发表时间：
2007-05-01
影响因子：
0.9
作者：
Banjoko, Sunny O;Sridhar Mynapelli, K C;Masheyi, Olatunde O
通讯作者：
Masheyi, Olatunde O
影响因子：
4.9
作者：
Frederick DW;McDougal AV;Semenas M;Vappiani J;Nuzzo A;Ulrich JC;Becherer JD;Preugschat F;Stewart EL;Sévin DC;Kramer HF
通讯作者：
Kramer HF
影响因子：
7.8
作者：
Christian CJ;Benian GM
通讯作者：
Benian GM