Metabolic Control and Aging-Jiangxi Key Laboratory of Aging and Diseases, Human Aging Research Institute (HARI), School of Life Science, Nanchang University, Nanchang 330031, China.
Biomolecules. 2024 Sep 2;14(9):1098. doi: 10.3390/biom14091098.
The regenerative capacity of muscle, which primarily relies on anabolic processes, diminishes with age, thereby reducing the effectiveness of therapeutic interventions aimed at treating age-related muscle atrophy. In this study, we observed a decline in the expression of methionine adenosine transferase 2A (MAT2A), which synthesizes S-adenosylmethionine (SAM), in the muscle tissues of both aged humans and mice. Considering MAT2A's critical role in anabolism, we hypothesized that its reduced expression contributes to the impaired regenerative capacity of aging skeletal muscle. Mimicking this age-related reduction in the MAT2A level, either by reducing gene expression or inhibiting enzymatic activity, led to inhibiting their differentiation into myotubes. , inhibiting MAT2A activity aggravated BaCl-induced skeletal muscle damage and decreased the number of satellite cells, whereas supplementation with SAM improved these effects. RNA-sequencing analysis further revealed that the Fas cell surface death receptor (Fas) gene was upregulated in -knockdown C2C12 cells. Suppressing MAT2A expression or activity elevated Fas protein levels and increased the proportion of apoptotic cells. Additionally, inhibition of MAT2A expression or activity increased p53 expression. In conclusion, our findings demonstrated that impaired MAT2A expression or activity compromised the regeneration and repair capabilities of skeletal muscle, partially through p53-Fas-mediated apoptosis.
肌肉的再生能力主要依赖于合成代谢过程，随着年龄的增长而减弱，从而降低了治疗与年龄相关的肌肉萎缩的治疗干预措施的效果。在这项研究中，我们观察到在衰老的人类和小鼠的肌肉组织中，蛋氨酸腺苷转移酶 2A（MAT2A）的表达下降，MAT2A 合成 S-腺苷甲硫氨酸（SAM）。鉴于 MAT2A 在合成代谢中的关键作用，我们假设其表达减少导致衰老骨骼肌再生能力受损。通过降低基因表达或抑制酶活性来模拟这种与年龄相关的 MAT2A 水平降低，导致其分化为肌管的能力受到抑制。抑制 MAT2A 活性加剧了 BaCl2 诱导的骨骼肌损伤，减少了卫星细胞的数量，而补充 SAM 则改善了这些作用。RNA 测序分析进一步显示，-knockdown C2C12 细胞中的 Fas 细胞表面死亡受体（Fas）基因上调。抑制 MAT2A 的表达或活性会增加 Fas 蛋白水平并增加凋亡细胞的比例。此外，抑制 MAT2A 的表达或活性会增加 p53 的表达。总之，我们的研究结果表明，受损的 MAT2A 表达或活性会损害骨骼肌的再生和修复能力，部分通过 p53-Fas 介导的细胞凋亡。
