Your competent? doctor has known of the myelin problem post stroke and already created protocols to fix that, right? Oh no, you DON'T have a functioning stroke doctor, do you? RUN AWAY!
Carlos Matute 1 2 3 carlos.matute@ehu.eus Alexei Verkhratsky1 2 3 4 alexej.verkhratsky@manchester.ac.uk
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Abstract
Central nervous system (CNS) myelin may act as a dynamic energy store that supports brain metabolism; its consumption and replenishment is a newly recognized form of metabolic plasticity aimed at maintaining brain function upon limited glucose supply. In this forum article we propose that myelin dysfunctions may affect human health in aging and neurodegenerative diseases. Keywords
myelin energy metabolism aging neurodegenerative diseases
Brain myelin contributes to energy metabolism
The CNS is highly vulnerable to metabolic stress due to its lack of substantial energy reserves. The small amounts of glycogen stored in astrocytes are insufficient to meet the brain’s energy demands, even for brief periods. Glucose is the brain’s obligatory energy substrate, metabolized to generate ATP via glycolysis in the cytosol and oxidative phosphorylation in mitochondria [1]. Interestingly, evolution has endowed the human brain with a remarkable adaptation: myelin, which accounts for approximately 50% of brain volume, giving the brain the highest fat content of any organ in the body. Fast action potential propagation along axons is energetically demanding. Myelin facilitates this process by acting as an electrical insulator and by providing both structural and trophic support to axons. Beyond these classical roles, myelin also contributes metabolically by supplying energy substrates, such as lactate, to meet axonal energy demands [2]. The axon–myelin unit therefore functions as a dynamic metabolic shuttle that sustains axonal health, while failure of this machinery may trigger pathological changes. Structurally, myelin is an extraordinarily lipid-rich membrane, composed of approximately 80% lipids. This high lipid content and the large volume of myelin in the CNS position it as a potential reservoir of fatty acids for energy production. Indeed, lipids are the body’s most abundant energy store, suggesting that myelin-derived fatty acids may help sustain CNS energy metabolism in both physiological and pathological conditions. Oligodendrocytes, the myelin-producing cells of the CNS, rely on both glycolysis and oxidative phosphorylation to maintain myelin and sustain axonal function. While the role of myelin lipids in energy metabolism remains incompletely understood, they may undergo β-oxidation in mitochondria or peroxisomes and thereby contribute to ATP production. Recent studies support this possibility. Under hypoglycemic conditions, myelin fatty acid levels decrease in mice [3] suggesting that their mobilization can compensate for glucose scarcity. In Drosophila melanogaster, which lacks myelin and instead stores lipids in the form of lipid droplets, nutrient restriction similarly triggers lipid mobilization as an alternative brain energy source [4]. This suggests that lipid use as a metabolic buffer is a conserved mechanism, possibly representing an ancestral energy storage strategy that evolved into myelin in vertebrates [5]. These findings imply that oligodendrocytes may respond to glucose deprivation by breaking down myelin to release fatty acids, thereby supplying alternative energy substrates to sustain axonal function. Recent evidence indicates that myelin is significantly reduced in specific brain regions following marathon running. These areas, involved in motor coordination and sensory–emotional integration, typically show myelin recovery within weeks. This reversible depletion supports the idea that myelin may function as a transient energy reservoir during periods of extreme metabolic demand. Similar patterns observed in conditions of undernutrition, such as anorexia, suggest a broader role for myelin in energy regulation. The potential for widespread utilization of myelin-derived fatty acids in ATP production is substantial (Figure 1A). Under conditions of glucose deprivation, regulated myelin turnover may serve as a transient source of metabolic support for axons. Notably, the consistent observation of cerebral hypometabolism in aging and neurodegenerative diseases leads us to hypothesize that progressive myelin loss plays a central and underappreciated role in driving the energy deficits characteristic of these conditions. In this forum article we examine the emerging evidence that supports this hypothesis. Brain myelin as an energy source and reservoir in health and disease.
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