Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Biophys J. 2013 Mar 5;104(5):1127-41. doi: 10.1016/j.bpj.2013.01.025.
Due to their role in cellular energetics and metabolism, skeletal muscle mitochondria appear to play a key role in the development of insulin resistance and type II diabetes. High-fat diet can induce higher levels of reactive oxygen species (ROS), evidenced by hydrogen peroxide (H2O2) emission from mitochondria, which may be causal for insulin resistance in skeletal muscle. The underlying mechanisms are unclear. Recent published data on single substrate (pyruvate, succinate, fat) metabolism in both normal diet (CON) and high-fat diet (HFD) states of skeletal muscle allowed us to develop an integrated mathematical model of skeletal muscle mitochondrial metabolism. Model simulations suggested that long-term HFD may affect specific metabolic reaction/pathways by altering enzyme activities. Our model allows us to predict oxygen consumption and ROS generation for any combination of substrates. In particular, we predict a synergy between (iso-membrane potential) combinations of pyruvate and fat in ROS production compared to the sum of ROS production with each substrate singly in both CON and HFD states. This synergy is blunted in the HFD state.
由于其在细胞能量学和代谢中的作用，骨骼肌线粒体似乎在胰岛素抵抗和 II 型糖尿病的发展中起着关键作用。高脂肪饮食可诱导更高水平的活性氧（ROS），这可通过线粒体产生的过氧化氢（H2O2）来证明，这可能是骨骼肌胰岛素抵抗的原因。其潜在机制尚不清楚。最近发表的关于骨骼肌在正常饮食（CON）和高脂肪饮食（HFD）状态下单一底物（丙酮酸、琥珀酸、脂肪）代谢的研究数据，使我们能够建立骨骼肌线粒体代谢的综合数学模型。模型模拟表明，长期 HFD 可能通过改变酶活性来影响特定的代谢反应/途径。我们的模型允许我们预测任何底物组合的耗氧量和 ROS 生成。特别是，与 CON 和 HFD 状态下每种底物单独使用相比，我们预测在 ROS 生成方面，（等膜电位）组合的丙酮酸和脂肪之间存在协同作用。这种协同作用在 HFD 状态下减弱。
