2-Hydroxypropanoic acid, 2-Hydroxypropionic acid
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Lactic acid is an organic acid and chiral molecule consisting of two optical isomers, L-lactic acid and D-lactic acid. In mammals, the conjugate base of lactic acid, lactate, is produced from pyruvate through glucose fermentation and is a byproduct of a process called glycolysis1. It is made in several organs, including skeletal muscle, the gut, the brain, skin, and red blood cells. During anaerobic exercise, most lactate is produced in skeletal muscle and the gut2. Conversely, the body can be exposed to D-lactic acid through contaminated food or the microbiota during some disease states.
Lactate has generated considerable attention for its roles in regulating glucose metabolism, maintenance of redox homeostasis, and modulation of fatty acid metabolism. Lactic acidosis (too much lactic acid in the blood) is a potential outcome of strenuous exercise and, therefore, the culprit behind muscle soreness. However, lactic acid buildup can also occur due to several diseases and disorders, including diabetes, cancer, liver disease, or heart failure3.
Under circumstances where aerobic conditions are not met for energy production, glycolysis is required for glucose breakdown. While lactate has received a bad reputation as a waste product, recent research has suggested that it is an active participant in glucose metabolism and is a supplementary source of energy when blood sugar levels are low4. Emerging research has demonstrated that lactate and lactic acid have widespread roles across mammalian physiology with roles in several health conditions.
Lactic acid and metabolic health
Metabolic disorders like obesity and type-2 diabetes have a profound impact on glucose metabolism. Considering the close association between glucose regulation and lactate, it is unsurprising that these metabolic disorders also have a robust effect on lactate homeostasis. Early studies demonstrated that obese individuals exhibit increased basal lactate levels5 that have since been linked to insulin resistance6. More recent data have demonstrated that elevated lactate levels trigger inflammation-related molecular pathways in adipose tissues, increasing circulating proinflammatory cytokines that in turn leads to insulin resistance in peripheral organs7.
Lactic acid and exercise
Lactate and lactic acid were once considered harmful compounds associated with muscle soreness following strenuous exercise, such as high-intensity interval training (HIIT). However, recent research suggests that lactate plays a more complex role in regulating the intersection between energy metabolism, metabolic health, and physical activity. For example, one study examined the effects of sprint training on energy metabolism in type-1 diabetics. Their findings revealed that while type-1 diabetics exhibit increased lactate levels before exercise, these individuals showed appropriate counterregulatory responses to metabolic destabilization (e.g., lower lactate, decreased ATP degradation, decreased glycolytic rates). Thus, despite impaired metabolic control in type-1 diabetics, high-intensity exercise can provide improved skeletal muscle oxidative capacity8.
Other studies have demonstrated that lactate is not only an important energy source for various cell types but can also participate in the regeneration of muscle fibers. For instance, it not only increases the expression of genes that are involved in mitochondrial regeneration9 but also increases proliferating cells and myotubes in muscles10. Collectively, lactate appears to confer both beneficial and harmful effects, and these outcomes largely depend on health conditions and physiological status.
Lactic acid, the gut microbiome, and the gut
Beyond skeletal muscle, lactate can also be produced by the gut microbiome. The gut microbiome consists of both healthy and harmful bacteria, and many of these bacteria produce metabolites that have broad effects on the body. The gut also contains bacteria capable of producing lactate (e.g., Lactobacillus and Bifidobacterium). Through other gut microbes, lactate can be converted into a variety of short-chain fatty acids (SCFAs) that are critical for maintaining energy metabolism11.
The beneficial effect of lactic acid-producing bacteria has been investigated in individuals with intestinal problems (e.g., constipation and diarrhea). Interestingly, supplementation with yogurt made from plant-derived lactic acid bacteria resulted in decreases in low-density lipoprotein cholesterol, enhanced intestinal health, and improved liver function12. Others have demonstrated that lactate and SCFAs (e.g., butyrate) confer these beneficial effects by decreasing proinflammatory responses in intestinal epithelial cells and myeloid cells13.
Lactic acid and the liver
As a critical component of glucose regulation, lactate also impacts liver function and health. As the muscles release lactate, it is delivered along with pyruvate to the liver for glucogenesis14. Individuals with liver injury often develop lactic acidosis that ultimately results in harmful impacts on the human body.
The liver is the key organ for lactate clearance, and research has demonstrated that diseased livers don’t efficiently clear lactate15. This leads to high lactic acid levels that ultimately lead to sepsis, gastrointestinal hemorrhage, and hepatic failure16. Interestingly, other reports involving high-intensity interval resistance training in mice demonstrated that this type of heavy exercise improves glycogenesis by increasing lactate clearance and lactate threshold17.
Lactic acid and the cardiovascular system
Lactate levels and lactic acidosis have been demonstrated to be effective markers for cardiovascular health and an indicator of complications following cardiac surgery. For instance, reports have found that high levels of lactate in patients following cardiac surgery were significantly associated with harmful outcomes, suggesting that bloodstream lactate might be a useful marker for monitoring post-cardiac surgery status18. Furthermore, others have demonstrated that increased lactate clearance is associated with decreased early mortality in post-cardiac arrest patients19.
Lactic acid and neuroscience
Lactate is also important for maintaining energy metabolism within the central nervous system (CNS). This is particularly evident in cerebral ischemia, a major mechanism that occurs during brain damage. When brain damage occurs, the lack of oxygen levels induces considerable glycolysis, resulting in the accumulation of lactate and lactic acidosis20. Lactic acidosis in the CNS ultimately results in swelling and death of neurons21.
Importantly, lactate in the CNS largely serves a protective role. Astrocytes, an important cell type in the brain, convert glycogen to lactate and transfer it to neighboring neurons. This allows neurons to delay ATP depletion during periods of intense exercise or hypoglycemia22. Similar to the role of lactate in other organs, brain lactate homeostasis is critical for maintaining regular energy metabolism, and excess lactate ultimately leads to detrimental impacts.
Lactic acid and drug development
The acidity of lactic acid (pH 4.2) has been utilized to maintain an acidic environment in pharmaceuticals. Notably, it is one of the active ingredients in Phexxi(R), an FDA-approved non-hormonal contraceptive. Phase III trials for Phexxi demonstrated that it is safe and effective (pregnancy rate of %4.1-13.65), and current Phase III trials are underway to evaluate its efficacy in treating sexually transmitted diseases23.
Lactic acid and cosmetics
Poly-L-lactic acid (PLLA) is a biocompatible polymer derived from lactic acid. It has seen considerable application in cosmetics and skincare, particularly in correcting volume loss associated with aging and is FDA-approved for HIV-associated facial lipoatrophy. In HIV-infected patients, PLLA is safe and has long-lasting effects, though some side effects include nodule and hematoma formation24. For cosmetic skincare, reports in HIV-negative participants indicated excellent volume correction with low nodule formation25.
Lactic acid in research
As of August 2023, there are over 300,000 citations for “lactic acid” and “lactate” in research publications (excluding books and documents) on Pubmed. The tremendous number of publications linking this metabolite to a broad range of physiological functions (several of which discussed here) suggests that any research program seeking to better understand metabolic, gastrointestinal, and neurological health may benefit from quantitative analysis of lactic acid or lactate. Considering the numerous effects of lactic acid and lactate on the human body, preclinical research may also benefit from lactic acid quantification for a comprehensive understanding of biomarkers, diagnosis, and disease monitoring.
- Li, X, Yang, Y, Zhang, B, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther 2022;(7):305.
- Wishart, DS, Guo, A, Oler, E, et al. HMDB 5.0: the Human Metabolome Database for 2022. Nucleic Acids Res 2022;(50):D622-D631.
- Kraut, JA, and Madias, NE. Lactic acidosis. N Engl J Med 2014;(371):2309-2319.
- Dienel, GA. Brain Glucose Metabolism: Integration of Energetics with Function. Physiol Rev 2019;(99):949-1045.
- Doar, JW, and Cramp, DG. The effects of obesity and maturity-onset diabetes mellitus on L(+) lactic acid metabolism. Clin Sci 1970;(39):271-279.
- Lovejoy, J, Newby, FD, Gebhart, SS, et al. Insulin resistance in obesity is associated with elevated basal lactate levels and diminished lactate appearance following intravenous glucose and insulin. Metabolism 1992;(41):22-27.
- Lin, Y, Bai, M, Wang, S, et al. Lactate Is a Key Mediator That Links Obesity to Insulin Resistance via Modulating Cytokine Production From Adipose Tissue. Diabetes 2022;(71):637-652.
- Harmer, AR, Chisholm, DJ, McKenna, MJ, et al. Sprint training increases muscle oxidative metabolism during high-intensity exercise in patients with type 1 diabetes. Diabetes Care 2008;(31):2097-2102.
- Nalbandian, M, Radak, Z, and Takeda, M. N-acetyl-L-cysteine Prevents Lactate-Mediated PGC1-alpha Expression in C2C12 Myotubes. Biology (Basel) 2019;(8).
- Oishi, Y, Tsukamoto, H, Yokokawa, T, et al. Mixed lactate and caffeine compound increases satellite cell activity and anabolic signals for muscle hypertrophy. J Appl Physiol (1985) 2015;(118):742-749.
- Markowiak-Kopec, P, and Slizewska, K. The Effect of Probiotics on the Production of Short-Chain Fatty Acids by Human Intestinal Microbiome. Nutrients 2020;(12).
- Higashikawa, F, Noda, M, Awaya, T, et al. Improvement of constipation and liver function by plant-derived lactic acid bacteria: a double-blind, randomized trial. Nutrition 2010;(26):367-374.
- Iraporda, C, Errea, A, Romanin, DE, et al. Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells. Immunobiology 2015;(220):1161-1169.
- Rui, L. Energy metabolism in the liver. Compr Physiol 2014;(4):177-197.
- De Jonghe, B, Cheval, C, Misset, B, et al. Relationship between blood lactate and early hepatic dysfunction in acute circulatory failure. J Crit Care 1999;(14):7-11.
- Heinig, RE, Clarke, EF, and Waterhouse, C. Lactic acidosis and liver disease. Arch Intern Med 1979;(139):1229-1232.
- Muller, GY, Matos, FO, Perego Junior, JE, et al. High-intensity interval resistance training (HIIRT) improves liver gluconeogenesis from lactate in Swiss mice. Appl Physiol Nutr Metab 2022;(47):439-446.
- Toraman, F, Evrenkaya, S, Yuce, M, et al. Lactic acidosis after cardiac surgery is associated with adverse outcome. Heart Surg Forum 2004;(7):E155-159.
- Donnino, MW, Miller, J, Goyal, N, et al. Effective lactate clearance is associated with improved outcome in post-cardiac arrest patients. Resuscitation 2007;(75):229-234.
- Silver, IA, Deas, J, and Erecinska, M. Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells. Neuroscience 1997;(78):589-601.
- Staub, F, Mackert, B, Kempski, O, et al. Swelling and death of neuronal cells by lactic acid. J Neurol Sci 1993;(119):79-84.
- Tekkok, SB, Brown, AM, Westenbroek, R, et al. Transfer of glycogen-derived lactate from astrocytes to axons via specific monocarboxylate transporters supports mouse optic nerve activity. J Neurosci Res 2005;(81):644-652.
- Su, S, and Vincent, KL. Lactic acid, citric acid, and potassium bitartrate non-hormonal prescription vaginal pH modulator (VPM) gel for the prevention of pregnancy. Expert Rev Clin Pharmacol 2022;(15):659-670.
- El-Beyrouty, C, Huang, V, Darnold, CJ, et al. Poly-L-lactic acid for facial lipoatrophy in HIV. Ann Pharmacother 2006;(40):1602-1606.
- Palm, MD, Woodhall, KE, Butterwick, KJ, et al. Cosmetic use of poly-l-lactic acid: a retrospective study of 130 patients. Dermatol Surg 2010;(36):161-170.