Ross Tilley Burn Centre Sunnybrook Health Sciences Centre Toronto, Ontario, M4N 3M5, Canada.
University of Toronto Toronto, Ontario, M5S 1A1, Canada.
Sci Rep. 2018 Apr 4;8(1):5646. doi: 10.1038/s41598-018-24017-7.
Thermal injury induces a complex immunometabolic response, characterized by hyperglycemia, extensive inflammation and persistent hypermetabolism. It has been suggested that attenuation of the hypermetabolic response is beneficial for patient wellbeing. To that effect, metformin represents an attractive therapeutic agent, as its effects on glycemia, inflammation and bioenergetics can improve outcomes in burn patients. Therefore, we studied metformin and its effects on mitochondrial bioenergetics in a murine model of thermal injury. We set out to determine the impact of this agent on mitochondrial hypermetabolism (adult mice) and mitochondrial dysfunction (aged mice). Seahorse respirometry complimented by in-gel activity assays were used to elucidate metformin's cellular mechanism. We found that metformin exerts distinctly different effects, attenuating the hypermetabolic mitochondria of adult mice while significantly improving mitochondrial bioenergetics in the aged mice. Furthermore, we observed that these changes occur both with and without adenosine monophosphate kinase (AMPK) activation, respectively, and analyzed damage markers to provide further context for metformin's beneficial actions. We suggest that metformin has a dual role following trauma, acting via both AMPK-dependent and independent pathways depending on bioenergetic status. These findings help further our understanding of metformin's biomolecular effects and support the continued use of this drug in patients.
热损伤会引起复杂的免疫代谢反应，其特征为高血糖、广泛的炎症和持续的高代谢。有研究表明，减轻高代谢反应对患者的健康有益。为此，二甲双胍是一种有吸引力的治疗药物，因为它对血糖、炎症和生物能量学的影响可以改善烧伤患者的预后。因此，我们研究了二甲双胍及其对热损伤小鼠模型中线粒体生物能量学的影响。我们旨在确定该药物对线粒体高代谢（成年小鼠）和线粒体功能障碍（老年小鼠）的影响。我们使用 Seahorse 呼吸仪和凝胶活性测定来阐明二甲双胍的细胞机制。我们发现，二甲双胍对成年小鼠的高代谢线粒体有明显的不同作用，而对老年小鼠的线粒体生物能量学有显著的改善作用。此外，我们观察到这些变化分别在有和没有腺苷单磷酸激酶（AMPK）激活的情况下发生，并分析了损伤标志物，为二甲双胍的有益作用提供了进一步的背景。我们认为，二甲双胍在创伤后具有双重作用，根据生物能量状态，通过 AMPK 依赖和非依赖途径发挥作用。这些发现有助于我们进一步了解二甲双胍的生物分子作用，并支持在患者中继续使用这种药物。
