Brain myelin as an energy source in humans

We recently found by magnetic resonance imaging that marathon runners undergo widespread myelin water fraction (MWF) decrease at completion of the effort. This reduction involves white and gray matter regions including primary motor and sensory cortical areas and pathways, as well as the corpus callosum and internal capsule. Notably, MWF levels recover within two months after the marathon. These results suggest that myelin use and replenishment is an unprecedented form of metabolic plasticity aimed at maintaining brain function during extreme conditions.

These findings challenge the commonly held view that neuronal function relies exclusively on glucose and oxygen supply, as the brain has no obvious energy stores, except for limited astrocyte glycogen. In addition, these data reveal that myelin consumption and replenishment may be a novel form of metabolic plasticity aimed at maintaining brain function during energy scarcity. Mechanistic details of how myelin lipids contribute to brain energy demand remains unknown and difficult to grasp. We are currently investigating how and under which circumstances may support brain energy demands.

Obtaining this knowledge may also help understanding brain function decline during ageing and neurodegenerative diseases, as waning glial support leading to synaptic, axonal and neuronal malfunctions may cause fuel shortage and metabolic deficits leading to nervous tissue damage.

Reference

• Ramos-Cabrer P, Cabrera-Zubizarreta A, Padro D, Matute-González M, Rodríguez-Antigüedad A, Matute C. Reversible reduction in brain myelin content upon marathon running. Nat Metab. 2025 Apr;7(4):697-703. doi: 10.1038/s42255-025-01244-7. Epub 2025 Mar 24. PMID: 40128612; PMCID: PMC12021653.

• Matute C., Ramos-Cabrer P.Reversible reduction in brain myelin content after endurance exercise. Nat Metab 7, 645–646 (2025). https://doi.org/10.1038/s42255-025-01251-8 

Impact of exercise in myelin structure and function 

Recent evidence suggests that myelin lipids may act as glial energy reserves when glucose is lacking, a hypothesis yet to be solidly proven. Recently, we examined the effects of running a marathon on myelin content by magnetic resonance imaging and found that marathon runners undergo widespread robust myelin decrease at completion of the effort. This reduction involves white and grey matter and includes primary motor and sensory cortical areas and pathways, as well as the entire corpus callosum and internal capsule. Notably, myelin levels partially recover within two weeks after the marathon. In the current proposal, we aim at studying the molecular and cellular events leading to myelin usage during physical exercise and storage thereafter at rest. For that purpose, we use prolonged running paradigms in mice using a technologically advanced running treadmill for healthy young adult and aged wildtype and transgenic mice lacking glucose transporters to selectively induce hypoglycaemia in oligodendroglia. Mice brains are analysed to determine in depth changes in myelin and oligodendrocyte statuses using 2-photon microscopy, high resolution immunofluorescence, and electron microscopy to assess changes in myelin structure, thickness, internode and node length plus channel expression. In turn, we also use neurophysiological techniques to assess function using as readouts compound action potential propagation in white matter and synaptic strength. Finally, we will evaluate behaviour to determine effects in motor functions, social interaction, and learning and memory tasks. Together, this project provides knowledge about the impact of endurance exercise in the brain, as well as new avenues about the contribution of myelin to brain metabolism and plasticity. The findings of this proposal may ultimately help devising nutritional strategies to promote brain health, and prevent cognitive dysfunction in aging and neurodegenerative diseases.

Funded by Basque Government.

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The role of myelin as a fuel in supporting oligodendroglia, axonal function and synaptic communication in health and disease

Myelin insulates axons to speed up nerve impulse propagation. In addition, recent evidence shows that oligodendrocytes, the makers of myelin in the Central Nervous System (CNS), supply axons with energy substrates to sustain the metabolic demand required for proper neuronal communication. As the CNS has not apparent energy stores apart from astrocyte glycogen, we postulate that myelin, which accounts for about 30% of the human brain mass, may constitute an important energy reservoir. Indeed, emerging data coming from our laboratory and other researchers strongly suggest that myelin may provide its main constituents, fatty acids (FAs), to fuel peroxisomes and mitochondria in axons and oligodendroglia.

In this proposal (MYELENERGY), we challenge the idea that myelin, in particular its FAs, may constitute a relevant energy source for fuelling fast axonal conduction and thus, proper synaptic function. In turn, myelin FAs may also contribute to the high energy demand of oligodendroglia for proliferation, differentiation, maturation and myelin turnover. Accordingly, we propose that a shortage of myelin FAs may impair remyelination after demyelination and cause axonal damage in demyelinating disorders such as multiple sclerosis. Specifically, we address the following objectives: i) to test the contribution of myelin FAs to axonal conduction in white matter; ii) to examine whether oligodendroglia use myelin FAs for energy production and lineage progression; iii) to explore the mechanisms regulating myelin consumption for energy production in oligodendroglia; and iv) to assess the impact of myelin FAs in synaptic communication. To address the goals of this project we use a vast array of techniques and experimental settings ranging from in vitro assays in wildtype and transgenic mice, to in-depth biological and ex vivo and in vivo imaging studies in well-established animal models of hypoglycaemia and multiple sclerosis. The proponent research team has multidisciplinary advanced expertise in oligodendrocyte and myelin biology. In addition, we have ongoing collaborations with top external international partners that contribute to the progress of the proposal by providing advice, equipment and by receiving in their laboratories and institutions junior and senior personnel.

This proposal is generating fundamental, transversal knowledge that will be instrumental to understand how myelin contributes to brain energy demands in physiology and pathological states. Importantly, the view of multiple sclerosis, and other demyelinating diseases, from a metabolic perspective may render new therapeutic avenues to slow its progression.

Funded by MICINN (Spanish Government).

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