Mohamed Junaith S, Hajira Ameena, Pardo Patricia S, Boriek Aladin M
Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX.
Diabetes. 2014 May;63(5):1546-59. doi: 10.2337/db13-1364.
High-fat diet (HFD) plays a central role in the initiation of mitochondrial dysfunction that significantly contributes to skeletal muscle metabolic disorders in obesity. However, the mechanism by which HFD weakens skeletal muscle metabolism by altering mitochondrial function and biogenesis is unknown. Given the emerging roles of microRNAs (miRNAs) in the regulation of skeletal muscle metabolism, we sought to determine whether activation of a specific miRNA pathway would rescue the HFD-induced mitochondrial dysfunction via the sirtuin-1 (SIRT-1)/ peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, a pathway that governs genes necessary for mitochondrial function. We here report that miR-149 strongly controls SIRT-1 expression and activity. Interestingly, miR-149 inhibits poly(ADP-ribose) polymerase-2 (PARP-2) and so increased cellular NAD(+) levels and SIRT-1 activity that subsequently increases mitochondrial function and biogenesis via PGC-1α activation. In addition, skeletal muscles from HFD-fed obese mice exhibit low levels of miR-149 and high levels of PARP-2, and they show reduced mitochondrial function and biogenesis due to a decreased activation of the SIRT-1/PGC-1α pathway, suggesting that mitochondrial dysfunction in the skeletal muscle of obese mice may be because of, at least in part, miR-149 dysregulation. Overall, miR-149 may be therapeutically useful for treating HFD-induced skeletal muscle metabolic disorders in such pathophysiological conditions as obesity and type 2 diabetes.
高脂饮食（HFD）在引发线粒体功能障碍中起核心作用，而线粒体功能障碍会显著导致肥胖状态下的骨骼肌代谢紊乱。然而，高脂饮食通过改变线粒体功能和生物发生来削弱骨骼肌代谢的机制尚不清楚。鉴于微小RNA（miRNA）在骨骼肌代谢调节中日益凸显的作用，我们试图确定激活特定的miRNA途径是否会通过沉默调节蛋白-1（SIRT-1）/过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）途径来挽救高脂饮食诱导的线粒体功能障碍，该途径控制着线粒体功能所需的基因。我们在此报告，miR-149强烈调控SIRT-1的表达和活性。有趣的是，miR-149抑制聚（ADP-核糖）聚合酶-2（PARP-2），从而提高细胞内烟酰胺腺嘌呤二核苷酸（NAD⁺）水平和SIRT-1活性，随后通过激活PGC-1α来增强线粒体功能和生物发生。此外，高脂饮食喂养的肥胖小鼠的骨骼肌中miR-149水平较低，PARP-2水平较高，并且由于SIRT-1/PGC-1α途径的激活减少，它们的线粒体功能和生物发生降低，这表明肥胖小鼠骨骼肌中的线粒体功能障碍可能至少部分是由于miR-149失调所致。总体而言，在肥胖和2型糖尿病等病理生理条件下，miR-149可能对治疗高脂饮食诱导的骨骼肌代谢紊乱具有治疗作用。
