Narine Mohanlall, Azmi Maryam A, Umali Martin, Volz Ashley, Colognato Holly
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, United States.
Program in Neurosciences, Stony Brook University, Stony Brook, NY, United States.
Front Cell Neurosci. 2023 Oct 12;17:1254303. doi: 10.3389/fncel.2023.1254303. eCollection 2023.
Multiple Sclerosis (MS) is a chronic disease characterized by immune-mediated destruction of myelinating oligodendroglia in the central nervous system. Loss of myelin leads to neurological dysfunction and, if myelin repair fails, neurodegeneration of the denuded axons. Virtually all treatments for MS act by suppressing immune function, but do not alter myelin repair outcomes or long-term disability. Excitingly, the diabetes drug metformin, a potent activator of the cellular "energy sensor" AMPK complex, has recently been reported to enhance recovery from demyelination. In aged mice, metformin can restore responsiveness of oligodendrocyte progenitor cells (OPCs) to pro-differentiation cues, enhancing their ability to differentiate and thus repair myelin. However, metformin's influence on young oligodendroglia remains poorly understood. Here we investigated metformin's effect on the temporal dynamics of differentiation and metabolism in young, healthy oligodendroglia and in oligodendroglia following myelin damage in young adult mice. Our findings reveal that metformin accelerates early stages of myelin repair following cuprizone-induced myelin damage. Metformin treatment of both isolated OPCs and oligodendrocytes altered cellular bioenergetics, but in distinct ways, oxidative phosphorylation and glycolysis in OPCs, but oxidative phosphorylation and glycolysis in both immature and mature oligodendrocytes. In addition, metformin accelerated the differentiation of OPCs to oligodendrocytes in an AMPK-dependent manner that was also dependent on metformin's ability to modulate cell metabolism. In summary, metformin dramatically alters metabolism and accelerates oligodendroglial differentiation both in health and following myelin damage. This finding broadens our knowledge of metformin's potential to promote myelin repair in MS and in other diseases with myelin loss or altered myelination dynamics.
多发性硬化症（MS）是一种慢性疾病，其特征是中枢神经系统中髓鞘形成少突胶质细胞受到免疫介导的破坏。髓鞘的丧失导致神经功能障碍，如果髓鞘修复失败，则会导致裸露轴突的神经变性。几乎所有治疗MS的方法都是通过抑制免疫功能起作用，但不会改变髓鞘修复结果或长期残疾状况。令人兴奋的是，糖尿病药物二甲双胍是细胞“能量传感器”AMPK复合物的有效激活剂，最近有报道称它能促进脱髓鞘后的恢复。在老年小鼠中，二甲双胍可以恢复少突胶质前体细胞（OPC）对促分化信号的反应能力，增强它们分化从而修复髓鞘的能力。然而，二甲双胍对年轻少突胶质细胞的影响仍知之甚少。在这里，我们研究了二甲双胍对年轻健康少突胶质细胞以及成年小鼠髓鞘损伤后少突胶质细胞分化和代谢的时间动态的影响。我们的研究结果表明，二甲双胍可加速由铜离子螯合剂诱导的髓鞘损伤后的髓鞘修复早期阶段。对分离的OPC和少突胶质细胞进行二甲双胍处理会改变细胞生物能量学，但方式不同，OPC中的氧化磷酸化和糖酵解受到影响，而未成熟和成熟少突胶质细胞中的氧化磷酸化和糖酵解均受到影响。此外，二甲双胍以依赖AMPK的方式加速OPC向少突胶质细胞的分化，这也依赖于二甲双胍调节细胞代谢的能力。总之，二甲双胍在健康状态下以及髓鞘损伤后都会显著改变代谢并加速少突胶质细胞分化。这一发现拓宽了我们对二甲双胍在MS以及其他伴有髓鞘丧失或髓鞘形成动力学改变的疾病中促进髓鞘修复潜力的认识。
