Lactate administration reproduces specific brain and liver exercise-related changes

Authors

  • Lezi E,

    1. University of Kansas Alzheimer's Disease Center, Kansas City, Kansas, USA
    2. Department of Physical Therapy and Rehabilitation Science, University of Kansas Medical Center, Kansas City, Kansas, USA
    Search for more papers by this author
  • Jianghua Lu,

    1. University of Kansas Alzheimer's Disease Center, Kansas City, Kansas, USA
    2. Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA
    Search for more papers by this author
  • J. Eva Selfridge,

    1. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
    Search for more papers by this author
  • Jeffrey M. Burns,

    1. University of Kansas Alzheimer's Disease Center, Kansas City, Kansas, USA
    2. Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA
    3. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
    Search for more papers by this author
  • Russell H. Swerdlow

    Corresponding author
    1. Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA
    2. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
    3. Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
    • University of Kansas Alzheimer's Disease Center, Kansas City, Kansas, USA
    Search for more papers by this author

Address correspondence and reprint requests to Russell H. Swerdlow, University of Kansas School of Medicine, MS 2012, Landon Center on Aging, 3901 Rainbow Blvd, Kansas City, KS 66160, USA. E-mail: rswerdlow@kumc.edu

Abstract

The effects of exercise are not limited to muscle, and its ability to mitigate some chronic diseases is under study. A more complete understanding of how exercise impacts non-muscle tissues might facilitate design of clinical trials and exercise mimetics. Here, we focused on lactate's ability to mediate changes in liver and brain bioenergetic-associated parameters. In one group of experiments, C57BL/6 mice underwent 7 weeks of treadmill exercise sessions at intensities intended to exceed the lactate threshold. Over time, the mice dramatically increased their lactate threshold. To ensure that plasma lactate accumulated during the final week, the mice were run to exhaustion. In the liver, mRNA levels of gluconeogenesis-promoting genes increased. While peroxisome proliferator-activated receptor-gamma co-activator 1 alpha (PGC-1α) expression increased, there was a decrease in PGC-1β expression, and overall gene expression changes favored respiratory chain down-regulation. In the brain, PGC-1α and PGC-1β were unchanged, but PGC-1-related co-activator expression and mitochondrial DNA copy number increased. Brain tumor necrosis factor alpha expression fell, whereas vascular endothelial growth factor A expression rose. In another group of experiments, exogenously administered lactate was found to reproduce some but not all of these observed liver and brain changes. Our data suggest that lactate, an exercise byproduct, could mediate some of the effects exercise has on the liver and the brain, and that lactate itself can act as a partial exercise mimetic.

image

In mice, exercise induces liver peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) mRNA, increases gluconeogenesis, but otherwise minimally affects respiration infrastructure. Brain PGC-1-related co-activator (PRC) mRNA, mitochondrial DNA (mtDNA), and vascular endothelial growth factor A (VEGF-A) mRNA increase, whereas tumor necrosis factor alpha (TNF-α) mRNA decreases. Lactate injection reproduces some, but not all, of these effects. Exercise-generated lactate, therefore, likely mediates some exercise-associated liver and brain effects.

Ancillary