Hydrogen sulfide mitigates skeletal muscle mitophagy-led tissue remodeling via epigenetic regulation of the gene writer and eraser function.
Hydrogen sulfide mitigates skeletal muscle mitophagy-led tissue remodeling via epigenetic regulation of the gene writer and eraser function.
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DOI：
10.14814/phy2.15422
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发表时间：
2022-08
影响因子：
2.5
通讯作者：
中科院分区：
文献类型：
--
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酮体（KB）作为线粒体生物遗传学的食物。有趣的是，已知益生菌促进肠道中KB的形成（特别是属于乳杆菌属的那些）。此外，乳酸杆菌有助于产生叶酸，降低同型半胱氨酸（Hcy）的水平;一种标志性的非蛋白质氨基酸，定义了表观遗传学及其景观的重要性。在这项研究中，我们决定测试硫化氢（H2S），另一种Hcy降低剂是否调节表观遗传基因作家DNA甲基转移酶（DNMT），擦除FTO和TET 2，从而减轻骨骼肌重塑。我们用NaHS（H2S供体）治疗高同型半胱氨酸血症（HHcy，胱硫醚β合酶杂合子敲除; CBS+/−）小鼠。结果表明，与WT对照小鼠（CBS+/+）相比，CBS+/−小鼠品系中的HHcy造成多器官损伤。H2S处理消除了大部分HHcy诱导的损伤。CBS+/−小鼠的基因编写者（DNMT 2）和H3 K9（甲基化）水平较高，H2S治疗使其水平正常化。更重要的是，CBS+/−小鼠的擦除FTO、泰特和相关GADD 45和MMP-13水平降低;然而，H2S处理减轻了它们各自的降低。这些事件与线粒体分裂有关，即，DRP 1和线粒体自噬的增加。尽管CBS+/-小鼠的MMP-2水平低于WT，但H2S可进一步降低CBS+/-小鼠的MMP-2水平。MMPs水平与CBS+/−骨骼肌间质纤维化增加相关。由于纤维化，CBS+/−小鼠的股动脉血流量减少，并通过H2S恢复正常。发现CBS+/−小鼠的骨骼和肌肉强度降低，但H2S治疗使CBS+/−小鼠的骨骼肌强度正常化。我们的研究结果表明，H2S通过基因写入器和擦除器功能的表观遗传调节减轻线粒体自噬导致的骨骼肌重塑。CBS−/+小鼠骨骼肌中的异常线粒体自噬通过H2S处理成功减轻。
Ketone bodies (KB) serve as the food for mitochondrial biogenetics. Interestingly, probiotics are known to promote KB formation in the gut (especially those that belong to the Lactobacillus genus). Furthermore, Lactobacillus helps produce folate that lowers the levels of homocysteine (Hcy); a hallmark non‐proteinogenic amino acid that defines the importance of epigenetics, and its landscape. In this study, we decided to test whether hydrogen sulfide (H2S), another Hcy lowering agent regulates the epigenetic gene writer DNA methyltransferase (DNMT), eraser FTO and TET2, and thus mitigates the skeletal muscle remodeling. We treated hyperhomocysteinemic (HHcy, cystathionine beta‐synthase heterozygote knockout; CBS+/−) mice with NaHS (the H2S donor). The results suggested multi‐organ damage by HHcy in the CBS+/−mouse strain compared with WT control mice (CBS+/+). H2S treatment abrogated most of the HHcy‐induced damage. The levels of gene writer (DNMT2) and H3K9 (methylation) were higher in the CBS+/− mice, and the H2S treatment normalized their levels. More importantly, the levels of eraser FTO, TET, and associated GADD45, and MMP‐13 were decreased in the CBS+/− mice; however, H2S treatment mitigated their respective decrease. These events were associated with mitochondrial fission, i.e., an increase in DRP1, and mitophagy. Although the MMP‐2 level was lower in CBS+/− compared to WT but H2S could further lower it in the CBS+/− mice. The MMPs levels were associated with an increase in interstitial fibrosis in the CBS+/− skeletal muscle. Due to fibrosis, the femoral artery blood flow was reduced in the CBS+/− mice, and that was normalized by H2S. The bone and muscle strengths were found to be decreased in the CBS+/− mice but the H2S treatment normalized skeletal muscle strength in the CBS+/− mice. Our findings suggest that H2S mitigates the mitophagy‐led skeletal muscle remodeling via epigenetic regulation of the gene writer and eraser function. Abnormal mitophagy in the CBS−/+ mice skeletal muscle is mitigated by the H2S treatment successfully.
影响因子：
3.7
作者：
Régnier V;Billard JM;Gupta S;Potier B;Woerner S;Paly E;Ledru A;David S;Luilier S;Bizot JC;Vacano G;Kraus JP;Patterson D;Kruger WD;Delabar JM;London J
通讯作者：
London J