Stancic Ana, Filipovic Milos, Ivanovic-Burmazovic Ivana, Masovic Sava, Jankovic Aleksandra, Otasevic Vesna, Korac Aleksandra, Buzadzic Biljana, Korac Bato
Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia.
University of Bordeaux IBGC, UMR 509, France.
Chem Biol Interact. 2017 Jun 25;272:188-196. doi: 10.1016/j.cbi.2017.05.003. Epub 2017 May 5.
Considering the vital role of skeletal muscle in control of whole-body metabolism and the severity of long-term diabetic complications, we aimed to reveal the molecular pattern of early diabetes-related skeletal muscle phenotype in terms of energy metabolism, focusing on regulatory mechanisms, and the possibility to improve it using two redox modulators, l-arginine and superoxide dismutase (SOD) mimic. Alloxan-induced diabetic rats (120 mg/kg) were treated with l-arginine or the highly specific SOD mimic, M40403, for 7 days. As appropriate controls, non-diabetic rats received the same treatments. We found that l-arginine and M40403 restored diabetes-induced impairment of phospho-5'-AMP-activated protein kinase α (AMPKα) signaling by upregulating AMPKα protein itself and its downstream effectors, peroxisome proliferator-activated receptor-γ coactivator-1α and nuclear respiratory factor 1. Also, there was a restitution of the protein levels of oxidative phosphorylation components (complex I, complex II and complex IV) and mitofusin 2. Furthermore, l-arginine and M40403 induced translocation of glucose transporter 4 to the membrane and upregulation of protein of phosphofructokinase and acyl coenzyme A dehydrogenase, diminishing negative diabetic effects on limiting factors of glucose and lipid metabolism. Both treatments abolished diabetes-induced downregulation of sarcoplasmic reticulum calcium-ATPase proteins (SERCA 1 and 2). Similar effects of l-arginine and SOD mimic treatments suggest that disturbances in the superoxide/nitric oxide ratio may be responsible for skeletal muscle mitochondrial and metabolic impairment in early diabetes. Our results provide evidence that l-arginine and SOD mimics have potential in preventing and treating metabolic disturbances accompanying this widespread metabolic disease.
鉴于骨骼肌在控制全身代谢中的重要作用以及长期糖尿病并发症的严重性，我们旨在揭示早期糖尿病相关骨骼肌在能量代谢方面的分子模式，重点关注调节机制，以及使用两种氧化还原调节剂（L-精氨酸和超氧化物歧化酶（SOD）模拟物）改善这种模式的可能性。用L-精氨酸或高度特异性的SOD模拟物M40403对四氧嘧啶诱导的糖尿病大鼠（120mg/kg）进行7天治疗。作为适当的对照，非糖尿病大鼠接受相同治疗。我们发现，L-精氨酸和M40403通过上调AMPKα蛋白本身及其下游效应物过氧化物酶体增殖物激活受体γ共激活因子-1α和核呼吸因子1，恢复了糖尿病诱导的磷酸化5'-AMP激活蛋白激酶α（AMPKα）信号传导损伤。此外，氧化磷酸化成分（复合物I、复合物II和复合物IV）和线粒体融合蛋白2的蛋白质水平也得到了恢复。此外，L-精氨酸和M40403诱导葡萄糖转运蛋白4向膜的转位，并上调磷酸果糖激酶和酰基辅酶A脱氢酶的蛋白质水平，减少糖尿病对葡萄糖和脂质代谢限制因素的负面影响。两种治疗均消除了糖尿病诱导的肌浆网钙ATP酶蛋白（SERCA 1和2）的下调。L-精氨酸和SOD模拟物治疗的类似效果表明，超氧化物/一氧化氮比例的紊乱可能是早期糖尿病骨骼肌线粒体和代谢损伤的原因。我们的结果提供了证据，表明L-精氨酸和SOD模拟物在预防和治疗伴随这种广泛代谢疾病的代谢紊乱方面具有潜力。
