Exercise-Induced Lactate Release Mediates Mitochondrial Biogenesis in the Hippocampus of Mice via Monocarboxylate Transporters

Abstract

Regular exercise training induces mitochondrial biogenesis in the brain via activation of peroxisome proliferator-activated receptor gamma-coactivator 1α (PGC-1α). However, it remains unclear whether a single bout of exercise would increase mitochondrial biogenesis in the brain. Therefore, we first investigated whether mitochondrial biogenesis in the hippocampus is affected by a single bout of exercise in mice. A single bout of high-intensity exercise, but not low- or moderate-intensity, increased hippocampal PGC-1α mRNA and mitochondrial DNA (mtDNA) copy number at 12 and 48h. These results depended on exercise intensity, and blood lactate levels observed immediately after exercise. As lactate induces mitochondrial biogenesis in the brain, we examined the effects of acute lactate administration on blood and hippocampal extracellular lactate concentration by in vivo microdialysis. Intraperitoneal (I.P.) lactate injection increased hippocampal extracellular lactate concentration to the same as blood lactate level, promoting PGC-1α mRNA expression in the hippocampus. However, this was suppressed by administering UK5099, a lactate transporter inhibitor, before lactate injection. I.P. UK5099 administration did not affect running performance and blood lactate concentration immediately after exercise but attenuated exercise-induced hippocampal PGC-1α mRNA and mtDNA copy number. In addition, hippocampal monocarboxylate transporters (MCT)1, MCT2, and brain-derived neurotrophic factor (BDNF) mRNA expression, except MCT4, also increased after high-intensity exercise, which was abolished by UK5099 administration. Further, injection of 1,4-dideoxy-1,4-imino-D-arabinitol (glycogen phosphorylase inhibitor) into the hippocampus before high-intensity exercise suppressed glycogen consumption during exercise, but hippocampal lactate, PGC-1α, MCT1, and MCT2 mRNA concentrations were not altered after exercise. These results indicate that the increased blood lactate released from skeletal muscle may induce hippocampal mitochondrial biogenesis and BDNF expression by inducing MCT expression in mice, especially during short-term high-intensity exercise. Thus, a single bout of exercise above the lactate threshold could provide an effective strategy for increasing mitochondrial biogenesis in the hippocampus.

Exercise and mitochondrial remodeling to prevent age-related neurodegeneration

“…Eight weeks of aerobic exercise training in mice increased PGC-1α mRNA expression ( 106 , 107 ) and protein ( 108 ). The increase in PGC-1α mRNA expression data was also noted after an acute bout of aerobic exercise ( 109 ). As discussed, there are clear limitations to concluding that these changes in PGC-1α resulted in changes to the turnover of mitochondrial proteins.…”

Melatonin Potentiates Exercise-Induced Increases in Skeletal Muscle PGC-1α and Optimizes Glycogen Replenishment

“…In this scenario, a rapid glycogen repletion following a bout of exhausting intense exercise is an important response to prepare the muscle for subsequent bouts of activity ( Wende et al, 2007 ), specially for sports with repeated bouts of exercise at the same day or in the following day. Thereby, melatonin seems to optimize the response to exercise since training adaptations reflect the accumulation of beneficial physiological functions produced from single bouts of exercise ( Park et al, 2021 ). Despite the positive results of this study, there are still some limitations that must be addressed: 1) We only focused on the master regulator of the mitochondrial biogenesis and its relationship with NRF-1; however, evaluating other proteins involved in the mitochondrial biogenesis process as well as the PGC-1 α downstream signals could provide additional information on the mechanism of action of melatonin; 2) we chose the dosage of 10 mg/kg due to the effects of melatonin on time to exhaustion ( t lim), as previously reported by our research group ( Beck et al, 2015A ; Beck et al, 2016 ; Faria et al, 2021 ); nonetheless, another concentration of melatonin should be tested to achieve a similar effect with lower dosage.…”

“…Hence, a rapid glycogen repletion following a bout of exhaustive exercise is an important adaptative response to prepare the muscle for subsequent efforts ( Wende et al, 2007 ), at least from a bioenergetic point of view. Moreover, to produce a better exercise training strategy it is essential to understand the beneficial effects of a single bout of exercise since training adaptations reflect the accumulation of beneficial physiological functions produced from acute exercise ( Park et al, 2021 ). Even though some studies suggest that melatonin exerts a modulatory role in muscle energy substrates immediately at the end of exercise ( Mazepa et al, 2000 ; Sanchez-Campos et al, 2001 ), decreasing carbohydrate utilization and increasing lipid utilization ( Mazepa et al, 2000 ), no study has investigated the effect of melatonin on the recovery of muscle glycogen and triglyceride contents at later times after an exhaustive bout of exercise at an individual and objective intensity.…”

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

“…As mentioned earlier, exercise has also been shown to stimulate mitochondrial biogenesis in the brain [ 292 , 293 ]. The exercise session typically consists of 25 to 30 min of cycling, alternating high-intensity activity with recovery by adjusting the resistance.…”