Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.
Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.
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DOI：
10.1016/j.cmet.2014.04.002
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发表时间：
2014-06-03
期刊：
影响因子：
29
通讯作者：
Auwerx J
中科院分区：
文献类型：
--
作者：
Pirinen E;Cantó C;Jo YS;Morato L;Zhang H;Menzies KJ;Williams EG;Mouchiroud L;Moullan N;Hagberg C;Li W;Timmers S;Imhof R;Verbeek J;Pujol A;van Loon B;Viscomi C;Zeviani M;Schrauwen P;Sauve AA;Schoonjans K;Auwerx J
我们先前证明，小鼠中聚（ADP-核糖）聚合酶（Parp）-1基因的缺失增强了氧化代谢，从而防止饮食诱导的肥胖。然而，PARP抑制剂增强线粒体功能的治疗用途仍有待探索。在这里，我们显示了在异质性小鼠群体中PARP-1表达和能量消耗之间的紧密负相关性，表明PARP-1活性的变化对代谢稳态有影响。值得注意的是，这些遗传相关性可以转化为药理学应用。PARP抑制剂的长期治疗通过增加线粒体呼吸复合物的丰度和增强线粒体呼吸能力来增强小鼠的适应性。此外，PARP抑制剂逆转了肥胖人初级肌管中的线粒体缺陷，并减弱了人成纤维细胞和C.优雅总的来说，我们的工作在蠕虫、小鼠和人类模型中验证了PARP抑制可用于治疗与线粒体功能缺陷相关的遗传性和获得性肌肉功能障碍。
We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.
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影响因子：
4.8
作者：
Senoo-Matsuda, N;Yasuda, K;Ishii, N
通讯作者：
Ishii, N
DOI：
10.1126/science.1243417
发表时间：
2013-11-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Peek CB;Affinati AH;Ramsey KM;Kuo HY;Yu W;Sena LA;Ilkayeva O;Marcheva B;Kobayashi Y;Omura C;Levine DC;Bacsik DJ;Gius D;Newgard CB;Goetzman E;Chandel NS;Denu JM;Mrksich M;Bass J
通讯作者：
Bass J
影响因子：
4.8
作者：
Erener, Sueheda;Mirsaidi, Ali;Hottiger, Michael O.
通讯作者：
Hottiger, Michael O.
影响因子：
4.8
作者：
Menzies, Keir J.;Singh, Kaustabh;Hood, David A.
通讯作者：
Hood, David A.
靶向Sirtuin 1以改善新陈代谢：您所需要的是NAD（+）？
影响因子：
21.1
作者：
Cantó C;Auwerx J
通讯作者：
Auwerx J