Modulating Glucose Metabolism and Lactate Synthesis in Injured Mouse Tendons: Treatment With Dichloroacetate, a Lactate Synthesis Inhibitor, Improves Tendon Healing.
Zhang Kairui,Hast Michael W,Izumi Soutarou,Usami Yu,Shetye Snehal,Akabudike Ngozi,Philp Nancy J,Iwamoto Masahiro,Nissim Itzhak,Soslowsky Louis J,Enomoto-Iwamoto Motomi
The American journal of sports medicine
BACKGROUND:Tendon injuries are common problems among athletes. Complete recovery of the mechanical structure and function of ruptured tendons is challenging. It has been demonstrated that upregulation of glycolysis and lactate production occurs in wounds, inflammation sites, and cancerous tumors, and these metabolic changes also control growth and differentiation of stem and progenitor cells. Similar metabolic changes have been reported in human healing tendons. In addition, lactate production has increased in progenitors isolated from injured tendons after treatment with IL-1β. It is thought that the metabolic changes play a role in tendon healing after injury. HYPOTHESIS:Glucose metabolism is altered during tendon injury and healing, and modulation of this altered metabolism improves tendon repair. STUDY DESIGN:Controlled laboratory study. METHODS:The authors used the tendon injury model involving a complete incision of the Achilles tendon in C57BL/6J female mice and studied alterations of glucose metabolism in injured tendons with [U-C]glucose and metabolomics analysis 1 and 4 weeks after surgery. They also examined the effects of dichloroacetate (DCA; an indirect lactate synthesis inhibitor) treatment on the recovery of structure and mechanical properties of injured tendons 4 weeks after surgery in the same mouse model. RESULTS:Significant changes in glucose metabolism in tendons after injury surgery were detected. C enrichment of metabolites and intermediates, flux through glycolysis, and lactate synthesis, as well as tricarboxylic acid cycle activity, were acutely increased 1 week after injury. Increased glycolysis and lactate generation were also found 4 weeks after injury. DCA-treated injured tendons showed decreased cross-sectional area and higher values of modulus, maximum stress, and maximum force when compared with vehicle-treated injured tendons. Improved alignment of the collagen fibers was also observed in the DCA group. Furthermore, DCA treatment reduced mucoid accumulation and ectopic calcification in injured tendons. CONCLUSION:The findings indicate that injured tendons acutely increase glycolysis and lactate synthesis after injury and that the inhibition of lactate synthesis by DCA is beneficial for tendon healing. CLINICAL RELEVANCE:Changing metabolism in injured tendons may be a therapeutic target for tendon repair.
10.1177/0363546518778789
Lactate in contemporary biology: a phoenix risen.
The Journal of physiology
After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell-cell and intracellular lactate shuttles fulfil purposes of energy substrate production and distribution, as well as cell signalling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signalling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristics such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signalling and shuttling are dysregulated as occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance in 21st century biology.
10.1113/JP280955
Lactate: the ugly duckling of energy metabolism.
Rabinowitz Joshua D,Enerbäck Sven
Nature metabolism
Lactate, perhaps the best-known metabolic waste product, was first isolated from sour milk, in which it is produced by lactobacilli. Whereas microbes also generate other fermentation products, such as ethanol or acetone, lactate dominates in mammals. Lactate production increases when the demand for ATP and oxygen exceeds supply, as occurs during intense exercise and ischaemia. The build-up of lactate in stressed muscle and ischaemic tissues has established lactate's reputation as a deleterious waste product. In this Perspective, we summarize emerging evidence that, in mammals, lactate also serves as a major circulating carbohydrate fuel. By providing mammalian cells with both a convenient source and sink for three-carbon compounds, circulating lactate enables the uncoupling of carbohydrate-driven mitochondrial energy generation from glycolysis. Lactate and pyruvate together serve as a circulating redox buffer that equilibrates the NADH/NAD ratio across cells and tissues. This reconceptualization of lactate as a fuel-analogous to how Hans Christian Andersen's ugly duckling is actually a beautiful swan-has the potential to reshape the field of energy metabolism.
10.1038/s42255-020-0243-4
The Multiple Roles of Lactate in the Skeletal Muscle.
Cells
Believed for a long time to be merely a waste product of cell metabolism, lactate is now considered a molecule with several roles, having metabolic and signalling functions together with a new, recently discovered role as an epigenetic modulator. Lactate produced by the skeletal muscle during physical exercise is conducted to the liver, which uses the metabolite as a gluconeogenic precursor, thus generating the well-known "Cori cycle". Moreover, the presence of lactate in the mitochondria associated with the lactate oxidation complex has become increasingly clear over the years. The signalling role of lactate occurs through binding with the GPR81 receptor, which triggers the typical signalling cascade of the G-protein-coupled receptors. Recently, it has been demonstrated that lactate regulates chromatin state and gene transcription by binding to histones. This review aims to describe the different roles of lactate in skeletal muscle, in both healthy and pathological conditions, and to highlight how lactate can influence muscle regeneration by acting directly on satellite cells.
10.3390/cells13141177
Activation of Lactate Receptor Positively Regulates Skeletal Muscle Mass in Mice.
Physiological research
G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has not been fully elucidated. As it has been reported that the lactate administration induces muscle hypertrophy, the stimulation of GPR81 has been suggested to mediate muscle hypertrophy. To clarify the contribution of GPR81 activation in skeletal muscle hypertrophy, in the present study, we investigated the effect of GPR81 agonist administration on skeletal muscle mass in mice. Male C57BL/6J mice were randomly divided into control group and GPR81 agonist-administered group that received oral administration of the specific GPR81 agonist 3-Chloro-5-hydroxybenzoic acid (CHBA). In both fast-twitch plantaris and slow-twitch soleus muscles of mice, the protein expression of GPR81 was observed. Oral administration of CHBA to mice significantly increased absolute muscle weight and muscle weight relative to body weight in the two muscles. Moreover, both absolute and relative muscle protein content in the two muscles were significantly increased by CHBA administration. CHBA administration also significantly upregulated the phosphorylation level of p42/44 extracellular signal-regulated kinase-1/2 (ERK1/2) and p90 ribosomal S6 kinase (p90RSK). These observations suggest that activation of GRP81 stimulates increased the mass of two types of skeletal muscle in mice in vivo. Lactate receptor GPR81 may positively affect skeletal muscle mass through activation of ERK pathway.
10.33549/physiolres.935004
[Lactate production contributes to development of fatigue during intense exercise in humans].
Bangsbo Jens,Hostrup Morten
Ugeskrift for laeger
Accumulation of muscle lactate and lowering of muscle pH during intense exercise do not per se cause fatigue during exercise, but it appears that they contribute to fatigue development in humans. This may be related to lowered muscle pH causing greater release of K+ from the contracting muscles and sensation of fatigue. Training elevates the capacity to release lactate and H+ as well as to buffer H+, probably contributing to the enhanced performance during intense exercise after a training period. In this review, we discuss the role of lactate and H+ for intense exercise performance in humans.
Physiological significance of elevated levels of lactate by exercise training in the brain and body.
Journal of bioscience and bioengineering
For the past 200 years, lactate has been regarded as a metabolic waste end product that causes fatigue during exercise. However, lactate production is closely correlated with energy metabolism. The lactate dehydrogenase-catalyzed reaction uses protons to produce lactate, which delays ongoing metabolic acidosis. Of note, lactate production differs depending on exercise intensity and is not limited to muscles. Importantly, controlling physiological effect of lactate may be a solution to alleviating some chronic diseases. Released through exercise, lactate is an important biomarker for fat oxidation in skeletal muscles. During recovery after sustained strenuous exercise, most of the lactate accumulated during exercise is removed by direct oxidation. However, as the muscle respiration rate decreases, lactate becomes a desirable substrate for hepatic glucose synthesis. Furthermore, improvement in brain function by lactate, particularly, through the expression of vascular endothelial growth factor and brain-derived neurotrophic factor, is being increasingly studied. In addition, it is possible to improve stress-related symptoms, such as depression, by regulating the function of hippocampal mitochondria, and with an increasingly aging society, lactate is being investigated as a preventive agent for brain diseases such as Alzheimer's disease. Therefore, the perception that lactate is equivalent to fatigue should no longer exist. This review focuses on the new perception of lactate and how lactate acts extensively in the skeletal muscles, heart, brain, kidney, and liver. Additionally, lactate is now used to confirm exercise performance and should be further studied to assess its impact on exercise training.
10.1016/j.jbiosc.2022.12.001
Lactate as a fulcrum of metabolism.
Brooks George A
Redox biology
Mistakenly thought to be the consequence of oxygen lack in contracting skeletal muscle we now know that the L-enantiomer of the lactate anion is formed under fully aerobic conditions and is utilized continuously in diverse cells, tissues, organs and at the whole-body level. By shuttling between producer (driver) and consumer (recipient) cells lactate fulfills at least three purposes: 1] a major energy source for mitochondrial respiration; 2] the major gluconeogenic precursor; and 3] a signaling molecule. Working by mass action, cell redox regulation, allosteric binding, and reprogramming of chromatin by lactylation of lysine residues on histones, lactate has major influences in energy substrate partitioning. The physiological range of tissue [lactate] is 0.5-20 mM and the cellular Lactate/Pyruvate ratio (L/P) can range from 10 to >500; these changes during exercise and other stress-strain responses dwarf other metabolic signals in magnitude and span. Hence, lactate dynamics have rapid and major short- and long-term effects on cell redox and other control systems. By inhibiting lipolysis in adipose via HCAR-1, and muscle mitochondrial fatty acid uptake via malonyl-CoA and CPT1, lactate controls energy substrate partitioning. Repeated lactate exposure from regular exercise results in major effects on the expression of regulatory enzymes of glycolysis and mitochondrial respiration. Lactate is the fulcrum of metabolic regulation in vivo.
10.1016/j.redox.2020.101454