Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Division of Endocrinology, Metabolism and Diabetes and Robley Rex VA Medical Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Physiol Rep. 2022 Aug;10(16):e15422. doi: 10.14814/phy2.15422.
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 (H S), 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 H S donor). The results suggested multi-organ damage by HHcy in the CBS mouse strain compared with WT control mice (CBS ). H S 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 H S 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, H S 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 H S 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 H S. The bone and muscle strengths were found to be decreased in the CBS mice but the H S treatment normalized skeletal muscle strength in the CBS mice. Our findings suggest that H S mitigates the mitophagy-led skeletal muscle remodeling via epigenetic regulation of the gene writer and eraser function.
酮体 (KB) 是线粒体生物发生的食物。有趣的是，益生菌已知可促进肠道中 KB 的形成（特别是属于乳杆菌属的那些）。此外，乳杆菌有助于产生叶酸，从而降低同型半胱氨酸 (Hcy) 的水平；这是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，我们决定测试另一种降低 Hcy 水平的物质——硫化氢 (H 2 S) 是否调节表观遗传基因书写者 DNA 甲基转移酶 (DNMT)、橡皮擦 FTO 和 TET2，从而减轻骨骼肌重塑。我们用 NaHS（H 2 S 供体）处理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 引起多器官损伤。H 2 S 治疗消除了 HHcy 诱导的大部分损伤。CBS 小鼠中的基因书写器 (DNMT2) 和 H3K9（甲基化）水平较高，H 2 S 治疗使其水平正常化。更重要的是，CBS 小鼠中的橡皮擦 FTO、TET 和相关的 GADD45 和 MMP-13 水平降低，但 H 2 S 治疗减轻了它们各自的降低。这些事件与线粒体裂变有关，即 DRP1 和自噬的增加。尽管 CBS 中的 MMP-2 水平低于 WT，但 H 2 S 可以进一步降低 CBS 小鼠中的 MMP-2 水平。MMPs 水平与 CBS 骨骼肌间质纤维化的增加有关。由于纤维化，CBS 小鼠的股动脉血流减少，而 H 2 S 使血流正常化。发现 CBS 小鼠的骨和肌肉力量下降，但 H 2 S 治疗使 CBS 小鼠的骨骼肌力量正常化。我们的研究结果表明，H 2 S 通过基因书写器和橡皮擦功能的表观遗传调节来减轻线粒体自噬引起的骨骼肌重塑。
