| dc.description.abstract | Exercise has been given credits for promoting health in general. Research show various exercise-induced benefits for brain in both humans and rodents, including improvement of cognitive function, increase of adult neurogenesis, and protection against the onset of neurodegenerative diseases. Despite these demonstrated beneficial effects, the underlying mechanisms are not clearly understood yet. Here, we hypothesize that muscle-generated lactate mediates some of the exercise-induced benefits on brain. Identification of the mechanisms will enable us to better apply exercise prescription clinically, and will also allow us to find a direction to develop exercise mimetics for older adults. The goal of this dissertation work is to evaluate effects of exercise training below and above the lactate threshold on brain health, explore the related mechanisms, and provide scientific evidence for developing exercise mimetics. In this work, we attempted to answer these questions from the perspective of brain bioenergetics. Chapter II was aimed to assess the effects of 6-week moderate-intensity exercise below the lactate threshold on liver and brain bioenergetic infrastructures in young adult mice. In liver, exercise training induced an increase in monocarboxylate transporter 2 (MCT2) expression which is responsible for liver lactate uptake, and this change was accompanied by increased liver expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1), sirtuin 1 (SIRT1), p38, and Complex IV subunit 4 (COX4), as well as increased AMP-activated protein kinase (AMPK) phosphorylation levels. Despite these changes, liver mitochondrial DNA (mtDNA) copy number and mitochondrial transcription factor A (TFAM) expression were reduced, suggesting the training shifted the liver's bioenergetic profile to promote gluconeogenesis, but not oxidative phosphorylation. The only altered brain parameter observed was a reduction in tumor necrosis factor alpha (TNF-α) expression. Brain bioenergetics were unlikely modified by moderate-intensity exercise. Our study showed that liver lactate import appears to be favored over brain lactate import, possibly limiting the ability, if any, of exercise-generated lactate to modify brain bioenergetics. We speculate that exercise-mediated effects on brain may be robust only when lactate production exceeds the lactate threshold. In order to test whether lactate mediates exercise-induced changes in brain, in Chapter III, we subjected young adult mice to 7-week supra-lactate threshold treadmill training (defined as training at exercise intensities above the lactate threshold). In liver, similar to what we found in studies described in Chapter II, training shifted the liver's bioenergetic profile to promote gluconeogenesis, and the expression levels of respiration-related genes were all down-regulated. In brain, PGC-1 related co-activator (PRC) expression and mtDNA copy number increased, suggesting mitochondrial biogenesis was induced by supra-lactate threshold treadmill training. Brain TNF-α expression fell, and vascular endothelial growth factor A (VEGF-A) expression increased. In another group of experiments, exogenously administered lactate over 14 days was found to reproduce some but not all of these observed liver and brain changes. Our data suggest that lactate is more than an exercise byproduct. It can mediate some of the exercise-induced changes in liver and brain, and lactate itself can act as a partial exercise mimetic. In Chapter IV, the effect of supra-lactate threshold exercise on brain mitochondrial biogenesis was demonstrated in aged mice as well. 19-month old mice were subjected to supra-lactate threshold intensive treadmill training for 8 weeks. Brain mitochondrial biogenesis was evidenced by increased brain PGC-1α and citrate synthase (CS) expression, as well as increased mtDNA content. Similar to the observations in young adult mice, a slight increase in brain VEGF-A expression was found in exercise group but brain TNF-α expression was unchanged. Our exercise training protocol did not affect aging-associated increase of plasma chemokine levels. In this study, we also tested the correlations between brain mitochondrial biogenesis, neurogenesis-related factors, and systemic/brain inflammatory factors to better understand the networking between exercise-induced benefits in brain, while no significant associations were detected. Nonetheless, together with the results from Chapter II and III, we conclude that supra-lactate threshold exercise training induces brain mitochondrial biogenesis in both young and aged mice. To investigate potential mechanisms of lactate's effects on brain bioenergetics, in Chapter V, we treated SH-SY5Y human neuronal cells with lactate. Our results showed that, lactate treatment significantly decreased glycolysis flux and had a prolonged enhancement of mitochondrial respiration. Exogenous lactate gradually shifted the bioenergetic metabolism towards a more aerobic state. These changes in bioenergetic fluxes were accompanied by increased expression of PGC-1β, nuclear respiratory factor 1 (NRF-1), and COX1, while mtDNA content was unchanged, indicating some components of mitochondrial biogenesis were up-regulated. Expression of VEGF-A was also increased. These lactate-induced effects were likely mediated by activation of AMPK, p38 mitogen-activated protein kinase (MAPK), and Akt signaling pathways to modify bioenergetic infrastructures. We also demonstrated that lactate treatment decreased mammalian target of rapamycin (mTOR) activation while increased forkhead box protein O1 (FOXO1) activation, implying a potential role for lactate in longevity. The results from this study provide novel insights into bioenergetics-based pharmacological therapies for neurodegenerative diseases with altered brain bioenergetic fluxes. In summary, this dissertation work suggests that exercise training above the lactate threshold is effective in promoting mitochondrial biogenesis, inducing expression of angiogenic/neurogenic factors, and/or reducing inflammation in mouse brains at different ages. Lactate seems to be mediating some of these changes, and appears to have additional beneficial effects including the modification of brain bioenergetic fluxes towards a healthier state. The results from this work have extensive therapeutic implications for persons with perturbed brain energy metabolism, such as Alzheimer's and Parkinson's diseases and other neurodegenerative disorders. | |
