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Abbreviation used
HIF-1α

hypoxia-inducible factor-1α

The case for exercise in brain health is continuing to deepen to the point where it seems the weight room is as critical for brain function as it is for building muscle mass. Increased cardiovascular function, improved psychological profile, increased neurotrophic factors, and neurogenesis are but a few of the factors linked to the benefits of vigorous exercise. A mechanistic understanding of how exercise can bring about such a pleotrophic range of changes has remained elusive prior to the study by Swerdlow and colleagues published in this issue of Journal of Neurochemistry (Lezi et al. 2013). Insightfully, these investigators used the most elementary product of exercise physiology, lactate, to mimic exercise. The authors found that lactate administered to resting mice produced many of the same benefits to brain mitochondria density found during extensive exercise (Fig. 1). This elegant and simple approach opens exercise benefits to pharmacological intervention, possibly with lactate analogs if not lactate itself. It also offers the hope that exercise mimetics can help those who cannot sustain vigorous exercise. Even more significantly, the findings link exercise to the observed benefits of pre-conditioning treatments. High lactate levels are usually considered a negative metabolic modulator, yet in Swerdlow's study the result indicates an increase in metabolic capacity. This apparent paradox, pre-conditioning, is a phenomenon whereby a sub-lethal condition protects against a subsequent potential lethal condition by stimulating endogenous adaptive and pro-survival events. As a matter of fact, hypoxia, as well as mitochondrial modulators such as cyanide, was shown to protect brain endothelial and neuronal cells against diabetes-mediated deleterious effects and other injurious conditions (Correia et al. 2011, 2012). However, an intriguing question can arise: what is the common denominator that explains the similar brain protective effects exerted by extensive exercise, exogenous lactate administration, and the pre-conditioning phenomenon? Despite the fact that at the end of animal treatments no significant alterations in hypoxia-inducible factor-1α (HIF-1α) mRNA and protein levels were observed, we strongly believe that this transcription factor may trigger the initial protective response mediated by extensive exercise and exogenous lactate administration (Fig. 1). And why HIF-1α? First and foremost, the abovementioned conditions (exercise, lactate, and pre-conditioning) per se are able to activate HIF-1α (Ameln et al. 2005; O'Hagan et al. 2009, De Saedeleer et al. 2012; Correia et al. 2011). Secondly, the metabolic switch from mitochondrial respiration towards glycolysis, to favor lactate production, is driven by HIF-1α. Third, recent advances in HIF-1α biology have revealed that the function of this fascinating transcription factor in the brain is not restricted to the regulation of energy metabolism; it also plays a role in the orchestration of several vital processes for normal brain functioning, including erythropoiesis, angiogenesis, and neurogenesis. Lastly, HIF-1α is a major piece that integrates the mitochondrial puzzle, being involved in the coordination of many aspects of mitochondrial life cycle and transport. For instance, HIF-1α regulates mitochondrial fusion–fission events, autophagy, and mitochondrial transport and distribution in neurons by favoring the mitochondrial trafficking in the anterograde direction. Interestingly, HIF-1α also facilitates mitochondrial biogenesis (Correia et al. 2011, 2013). Within this scenario, further studies focusing on the dynamic behavior of HIF-1α gene expression during extensive exercise and lactate treatment as well as the genetic manipulation of HIF-1α expression are required to help shed light on the mechanistic basis underlying the brain protective effects shared by exercise and exogenous lactate administration.

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Figure 1. Schematic representation of the brain adaptive response to extensive exercise and lactate. Extensive exercise per se has the capacity to enhance plasma lactate levels. At the brain level, exercise also promotes an increase in vascular endothelial growth factor A (VEGF-A) and peroxisome proliferator-activated receptor gamma co-activator 1 related co-activator (PGC-1α) expression that is accompanied by a rise in mitochondrial density. Notably, these effects are mimicked by the exogenous administration of lactate. However, the question remains to identify the mechanistic mediator of this adaptive response of the brain to extensive exercise and lactate.

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By means of metabolomics studies of the brain, connecting it to general fitness via one of the simplest of elements, lactate, Swerdlow and collaborators establish a direct link between exercise, lactate and metabolic enhancement. This area of research is likely to flourish with the application of further mechanistic and therapeutic approaches. It is certainly tempting to wonder if the benefits of dietary restriction, which is postulated to delay the progression of age-related neurodegenerative disorders, are similarly mediated by metabolic intermediates leading to a pre-conditioning-like phenomenon.

Novel insights leading to therapeutics cannot come too quickly for the millions suffering metabolic brain diseases such as Alzheimer's disease. Past approaches focused on blocking amyloid have failed repeatedly by neglecting to consider the elegant homeostatic mechanisms at work which allow the brain to function by adapting to new conditions. For most of us, the greatest stresses of life are the changes related to aging; amyloid could be a pre-conditioning response critical to brain function during aging. Indeed, amyloid has several physiological functions, including modulation of synaptic function, facilitation of neuronal growth and survival, protection against oxidative stress, and surveillance against neuroactive compounds, toxins and pathogens (Bishop and Robinson 2004). Particularly, the induction of HIF-1α by physiological levels of amyloid was shown to render neurons resistant to high levels of amyloid by promoting a shift in the energy metabolism. Amyloid-resistant neurons exhibit an enhanced flux of glucose through both the glycolytic pathway and the hexose monophosphate shunt (Soucek et al. 2003). Thus, the approach of amyloid removal could be as simplistic as removal of lactate as a means of reducing metabolic stress, when it is essential to signal metabolic enhancement. The increasing evidence of Alzheimer's and other brain diseases being metabolic disorders and the increased frequency of metabolic syndrome require the scientific community to bring new understanding to a problem we all face. While lactate pills may not replace a gym, a clear understanding of the mechanism might help us work with, rather than against, brain physiology in addressing chronic disease.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. References

Support was provided by the National Institute on Minority Health and Health Disparities (G12MD007591) from the National Institutes of Health, and by the Semmes Foundation. The authors have no conflicts of interest to declare.

References

  1. Top of page
  2. Acknowledgements
  3. References
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