Padro, D. | Search bioRxiv

bioRxiv2023

Widespread drastic reduction of brain myelin content upon prolonged endurance exercise

Recent evidence suggests that myelin lipids may act as glial energy reserves when glucose is lacking, a hypothesis yet to be solidly proven. Hereby, we examined the effects of running a marathon on the myelin content by MRI. Our findings show that marathon runners undergo widespread robust myelin decrease at completion of the effort. This reduction involves white and gray 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. These results reveal that myelin use and replenishment is an unprecedented form of metabolic plasticity aimed to maintain brain function during extreme conditions. One-Sentence SummaryBrain myelin usage during strenuous exercise and recovery thereafter

neuroscience↗

bioRxiv2023

Weak neuronal glycolysis sustains cognition and organismal fitness

The energy cost of neuronal activity is mainly sustained by glucose1,2. However, in an apparent paradox, neurons only weakly metabolize glucose through glycolysis3,4,5,6, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (Pfkfb3)3,7,8, a key glycolysis-promoting enzyme. To evaluate the in vivo physiological significance of this hypo-glycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression. In vivo molecular, biochemical, and metabolic flux analyses of these neurons revealed an accumulation of anomalous mitochondria, complex I disassembly, bioenergetic deficiency and mitochondrial redox stress. Notably, glycolysis-mediated NAD+ reduction impaired sirtuin-dependent autophagy. Furthermore, these mice displayed cognitive decline and a metabolic syndrome that was mimicked by confining Pfkfb3 expression to hypothalamic neurons. Neuron-specific genetic ablation of mitochondrial redox stress corrected these alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions.

cell biology↗