SIRT3调控线粒体质量在骨骼肌运动损伤与修复中的作用研究

Oxidative stress induced mitochondrial dysfunction may play an important role in skeletal muscle injury. Mitochondrial quality control has become a key mechanism that maintaining skeletal muscle homeostasis. However, how to repair and degradation of damaged mitochondria in skeletal muscle is still unclear. SIRT3 is an important deacetylase located in mitochondrion. Our previous studies have found that endurance exercise can increase the expression of SIRT3 along with the improvement of mitochondrial oxidative phosphorylation function; and exhaustive exercise led to a decline SIRT3 expression and mitochondrial oxidative damage in skeletal muscle. We presume that SIRT3 may be involved in the protective effects on skeletal muscle injury.This study aimed to investigate: effects of SIRT3 on mitochondrial oxidative stress; effects of SIRT3 on mitochondrial quality control involved in mitochondrial fusion, fission and autophagy; effects of overexpression of SIRT3 on skeletal muscle injury. This study would clarify the relationship among SIRT3, mitochondrial quality control and skeletal muscle injury. Activation of SIRT3 may be a promising target for the treatment of sports fatigue.

氧化应激导致的线粒体功能障碍是骨骼肌运动性损伤发生的主要原因，而线粒体质量控制是维持骨骼肌稳态效应的关键机制。但骨骼肌如何感知、修复和降解受损线粒体，并提高线粒体的生物合成的机制尚不清楚。SIRT3是存在于线粒体内重要的去乙酰化酶，我们前期研究发现耐力运动可上调骨骼肌SIRT3的表达伴随线粒体氧化磷酸化功能的提高；而力竭运动导致骨骼肌SIRT3表达的下降及线粒体的氧化损伤。由此，提出SIRT3可能通过调控线粒体的质量参与骨骼肌的损伤和修复的假设。本项目以线粒体质量调控为切入点，采用力竭跑台运动训练建立骨骼肌运动损伤动物模型, 研究1）SIRT3对骨骼肌线粒体氧化应激的作用；2）SIRT3对骨骼肌线粒体分裂、融合和自噬的作用； 3）过表达SIRT3对骨骼肌损伤修复的作用。进一步阐明SIRT3-线粒体质量控制-骨骼肌氧化损伤之间的关系，为防治骨骼肌运动性损伤开辟新的视角。

线粒体氧化应激导致的功能障碍是引发骨骼肌运动性损伤的主要机制。SIRT3是存在于线粒体内重要的去乙酰化酶，但对于SIRT3如何整合线粒体自由基代谢，调控骨骼肌的稳态机理尚不清楚。本项目以线粒体质量控制为切入点，采用力竭跑台运动训练建立骨骼肌运动损伤的动物模型, 我们研究发现SIRT3的下降伴随骨骼肌自噬相关性蛋白的高度乙酰化，从而抑制线粒体自噬，导致损伤线粒体的大量积聚，促使线粒体氧化应激产物增加及代谢功能障碍。SIRT3的过表达可参与修复骨骼肌运动损伤包括炎性变，及骨骼肌纤维代谢类型的转变。阐明SIRT3-线粒体质量控制-骨骼肌氧化损伤之间的关系，为防治骨骼肌运动性损伤开辟新的视角。