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第IIa类HDAC抑制细胞死亡途径,并保护肌肉完整性,以应对脂毒性

Sheree D Martin¹, Timothy Connor¹, Andrew Sanigorski¹

¹Institute for Mental and Physical Heath and Clinical Translation (IMPACT) and Metabolic Research Unit, School of Medicine, Deakin University, Geelong, VIC, 3216, Australia.

Cell death & disease

|December 1, 2023

概括

脂毒性会通过增加HDAC4和HDAC5.5来损害骨肌肉的新陈代谢. 这些酶减少氧化代谢和细胞死亡途径,保持肌肉细胞活力,但减少肌肉质量.

科学领域:

生物化学生物化学
细胞生物学细胞生物学
代谢过程中的代谢.

背景情况:

脂毒性,非脂肪组织中的脂质积累,破坏了骨肌肉的新陈代谢.
骨肌肉中脂毒性背后的精确机制尚未完全理解.

研究的目的:

为了研究基因素脱乙酶4和5 (HDAC4和HDAC5) 在脂毒性诱导的骨肌肉代谢变化中的作用.
阐明HDAC4和HDAC5在脂毒性期间对亡,铁亡和肌肉细胞活力的影响.

主要方法:

在对脂毒性的反应中评估了基因素脱乙酶4 (HDAC4) 和基因素脱乙酶5 (HDAC5) 表达的变化.
分析了HDAC4和HDAC5对代谢基因表达和线粒体功能的影响.
研究了对p53乙化的影响及其在亡中的作用.
检查了铁灭的途径和氧化还原驱动因素.
在肥胖的db/db小鼠模型中利用功能丧失的HDAC4和HDAC5突变.

主要成果:

脂毒性导致骨肌中的HDAC4和HDAC5水平升高.
增加的HDAC4/5降低了代谢基因表达和氧化代谢,有利于非氧化葡萄糖代谢.
这种重编程损害了亡和铁亡,但保留了肌肉细胞的活力.
在db/db小鼠中的HDAC4/5过度表达增强了氧化能力,增加了细胞死亡,并减少了肌肉质量.

结论:

HDAC4和HDAC5作为骨肌肉氧化代谢的关键抑制剂.
这些酶抑制细胞死亡途径 (细胞亡和铁亡),在脂毒条件下促进肌肉完整性.
准HDAC4和HDAC5可能为骨肌中的代谢功能障碍提供治疗策略.

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