Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH 441952, United States of America.
Anesthesia and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, United States of America.
Exp Neurol. 2022 Nov;357:114173. doi: 10.1016/j.expneurol.2022.114173. Epub 2022 Jul 19.
The astrocyte-neuron lactate shuttle (ANLS) is an essential metabolic support system that uptakes glucose, stores it as glycogen in astrocytes, and provides glycogen-derived lactate for axonal function. Aging intrinsically increases the vulnerability of white matter (WM) to injury. Therefore, we investigated the regulation of this shuttle to understand vascular-glial metabolic coupling to support axonal function during aging in two different WM tracts. Aging astrocytes displayed larger cell bodies and thicker horizontal processes in contrast to thinner vertically oriented processes of young astrocytes. Aging axons recovered less following aglycemia in mouse optic nerves (MONs) compared to young axons, although providing lactate during aglycemia equally supported young and aging axonal function. Incubating MONs in high glucose to upregulate glycogen stores in astrocytes delayed loss of function during aglycemia and improved recovery in both young and aging axons. Providing lactate during recovery from aglycemia unmasked a metabolic switch from glucose to lactate in aging axons. Young and aging corpus callosum consisting of a mixture of myelinated and unmyelinated axons sustained their function fully when lactate was available during aglycemia and surprisingly showed a greater resilience to aglycemia compared to fully myelinated axons of optic nerve. We conclude that lactate is a universal substrate for axons independent of their myelination content and age.
星形胶质细胞-神经元乳酸穿梭 (ANLS) 是一种重要的代谢支持系统，它摄取葡萄糖，将其储存为星形胶质细胞中的糖原，并为轴突功能提供糖原衍生的乳酸。衰老会内在增加白质 (WM) 对损伤的脆弱性。因此，我们研究了这种穿梭的调节，以了解血管-神经胶质代谢偶联，以支持在两个不同的 WM 束中衰老过程中的轴突功能。与年轻的星形胶质细胞的垂直定向的较薄的过程相比，衰老的星形胶质细胞的细胞体更大，水平过程更厚。与年轻的轴突相比，衰老的轴突在 MONs（鼠视神经）中的低糖血症后恢复较少，尽管在低糖血症期间提供乳酸同样支持年轻和衰老的轴突功能。在 MONs 中孵育高葡萄糖以增加星形胶质细胞中的糖原储存，可延迟低糖血症期间的功能丧失，并改善年轻和衰老的轴突的恢复。在低糖血症后的恢复期间提供乳酸揭示了衰老轴突中从葡萄糖到乳酸的代谢转换。由有髓鞘和无髓鞘轴突混合组成的年轻和衰老的胼胝体在低糖血症期间有乳酸可用时完全维持其功能，并且令人惊讶的是，与视神经的完全有髓鞘轴突相比，它们对低糖血症具有更大的抵抗力。我们得出结论，乳酸是轴突的通用底物，与它们的髓鞘化含量和年龄无关。
