Conditional Knockout of Pdha1 in Mouse Hippocampus Impairs Cognitive Function: The Possible Involvement of Lactate

Background and Purpose: Neurodegenerative diseases are associated with metabolic disturbances. Pyruvate dehydrogenase E1 component subunit alpha (PDHA1) is an essential component in the process of glucose metabolism, and its deficiency exists in various diseases such as Alzheimer’s disease (AD), epilepsy, Leigh’s syndrome, and diabetes-associated cognitive decline. However, the exact role of PDHA1 deficiency in neurodegenerative diseases remains to be elucidated. In this study, we explored the effect of PDHA1 deficiency on cognitive function and its molecular mechanism.Methods: A hippocampus-specific Pdha1 knockout (Pdha1–/–) mouse model was established, and behavioral tests were used to evaluate the cognitive function of mice. Transmission electron microscopy (TEM) was performed to observe the morphological changes of the hippocampus. The lactate level in the hippocampus was measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to explore the possible mechanism of the effect of PDHA1 on cognition.Results:Pdha1 knockout damaged the spatial memory of mice and led to the ultrastructural disorder of hippocampal neurons. Lactate accumulation and abnormal lactate transport occurred in Pdha1–/– mice, and the cyclic AMP-protein kinase A-cAMP response element-binding protein (cAMP/PKA/CREB) pathway was inhibited.Conclusion: Lactate accumulation caused by PDHA1 deficiency in the hippocampus may impair cognitive function by inhibiting the cAMP/PKA/CREB pathway.

The Acute Effect of Hyperoxia on Onset of Blood Lactate Accumulation (OBLA) and Performance in Female Runners during the Maximal Treadmill Test

The objective of this study was to analyze the acute effect of hyperoxia during the maximal treadmill test (MTT) of runners. Participants included 10 female street runners who performed the MTT under two different conditions: hyperoxia (HYPX), inhaling oxygen (60% O2) every 3 min; and normoxia (NORM), without additional oxygen inhalation. Both groups performed the MTT with increases in the slope of the run every 3 min until voluntary exhaustion. The variables of lactate concentration, the onset of blood lactate accumulation (OBLA), peripheral oxygen saturation (SpO2), heart rate (HR), and Borg scale were evaluated. It was verified after the comparison (HYPX vs. NORM) that stage 3 (p = 0.012, Cohen’s d = 1.76) and stage 4 (p < 0.001; Cohen’s d = 5.69) showed a reduction in lactate under the HYPX condition. OBLA under the HYPX condition was identified at a later stage than NORM. There were no differences in Borg scale, SpO2, and HR between the different conditions. It was concluded that the HYPX condition contributed to a reduction in lactate concentration and delayed OBLA in runners.

Effect of Uphill Running on VO2, Heart Rate and Lactate Accumulation on Lower Body Positive Pressure Treadmills

Lower body positive pressure treadmills (LBPPTs) as a strategy to reduce musculoskeletal load are becoming more common as part of sports conditioning, although the requisite physiological parameters are unclear. To elucidate their role, ten well-trained runners (30.2 ± 3.4 years; VO2max: 60.3 ± 4.2 mL kg−1 min−1) ran at 70% of their individual velocity at VO2max (vVO2max) on a LBPPT at 80% body weight support (80% BWSet) and 90% body weight support (90% BWSet), at 0%, 2% and 7% incline. Oxygen consumption (VO2), heart rate (HR) and blood lactate accumulation (LA) were monitored. It was found that an increase in incline led to increased VO2 values of 6.8 ± 0.8 mL kg−1 min−1 (0% vs. 7%, p < 0.001) and 5.4 ± 0.8 mL kg−1 min−1 (2% vs. 7%, p < 0.001). Between 80% BWSet and 90% BWSet, there were VO2 differences of 3.3 ± 0.2 mL kg−1 min−1 (p < 0.001). HR increased with incline by 12 ± 2 bpm (0% vs. 7%, p < 0.05) and 10 ± 2 bpm (2% vs. 7%, p < 0.05). From 80% BWSet to 90% BWSet, HR increases of 6 ± 1 bpm (p < 0.001) were observed. Additionally, LA values showed differences of 0.10 ± 0.02 mmol l−1 between 80% BWSet and 90% BWSet. Those results suggest that on a LBPPT, a 2% incline (at 70% vVO2max) is not yet sufficient to produce significant physiological changes in VO2, HR and LA—as opposed to running on conventional treadmills, where significant changes are measured. However, a 7% incline increases VO2 and HR significantly. Bringing together physiological and biomechanical factors from previous studies into this practical context, it appears that a 7% incline (at 80% BWSet) may be used to keep VO2 and HR load unchanged as compared to unsupported running, while biomechanical stress is substantially reduced.

Distribution, organization and expression of genes concerned with anaerobic lactate-utilization in human intestinal bacteria

Lactate accumulation in the human gut is linked to a range of deleterious health impacts. However, lactate is consumed and converted to the beneficial short chain fatty acids butyrate and propionate by indigenous lactate-utilizing bacteria. To better understand the underlying genetic basis for lactate utilization, transcriptomic analysis was performed for two prominent lactate-utilizing species from the human gut, Anaerobutyricum soehngenii and Coprococcus catus, during growth on lactate, hexose sugar, or hexose plus lactate. In A. soehngenii L2-7, six genes of the lct cluster including NAD-independent D-lactate dehydrogenase (i-LDH) were co-ordinately upregulated during growth on equimolar D and L-lactate (DL-lactate). Upregulated genes included an acyl-CoA dehydrogenase related to butyryl-CoA dehydrogenase, which may play a role in transferring reducing equivalents between reduction of crotonyl-CoA and oxidation of lactate. Genes upregulated in C. catus GD/7 included a six-gene cluster (lap) encoding propionyl CoA-transferase, a putative lactoyl-CoA epimerase, lactoyl-CoA dehydratase and lactate permease, and two unlinked acyl-CoA dehydrogenase genes that are candidates for acryloyl-CoA reductase. An i-LDH homolog in C. catus is encoded by a separate, partial lct, gene cluster, but not upregulated on lactate. While C. catus converts three mols of DL-lactate via the acrylate pathway to two mols propionate and one mol acetate, some of the acetate can be re-used with additional lactate to produce butyrate. A key regulatory difference is that while glucose partially repressed lct cluster expression in A. soehngenii, there was no repression of lactate utilization genes by fructose in the non-glucose utilizer C. catus. This implies that bacteria such as C. catus might be more important in curtailing lactate accumulation in the gut.