What is Dr. Zubair Khalid's research focus?

Dr. Zubair Khalid specializes in molecular virology, mRNA vaccine development, and computational biology, with a focus on avian pathogens like IBDV and Avian Reovirus.

Where is Dr. Zubair Khalid currently working?

Dr. Zubair Khalid is a Postdoctoral Research Associate at the University of Maryland (UMD), specifically within the Department of Animal and Avian Sciences.

What Is Lactic Acid? Production and Build-Up

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-09-19

Lactic acid is the protonated, acidic form of lactate, a three-carbon hydroxy acid produced when pyruvate is reduced by lactate dehydrogenase (LDH) during glycolysis. At the pH of blood and cytoplasm (roughly 7.0 to 7.4), more than 99 percent of the molecule exists as the deprotonated anion lactate plus a free proton, so "lactic acid" and "lactate" are not interchangeable in a chemistry sense even though clinicians use them loosely.

Lactate matters because it sits at the intersection of three things students are tested on: energy metabolism, acid-base physiology, and organ crosstalk. It is the end product of a pathway that can generate ATP without oxygen, it is a circulating fuel that the heart and liver consume, and it is a signaling molecule that modifies histones and metabolic enzymes through a post-translational mark called lactylation [1][2]. It is also the analyte behind one of the most common point-of-care tests in emergency medicine, where a rising blood lactate flags hypoperfusion before blood pressure falls.

The Chemistry: Why "Lactic Acid" and "Lactate" Are Not the Same Thing

Lactate is the conjugate base of lactic acid. The pKa of the lactic acid carboxyl group is about 3.86, which means that in any biological fluid near neutral pH, the equilibrium sits overwhelmingly on the lactate side. Every molecule of lactic acid that is produced immediately releases a proton (H+) and becomes lactate.

That proton release is the entire reason lactic acidosis exists. The acidosis is not caused by lactate itself. It is caused by the hydrogen ions that accompany lactate production, plus the failure of buffering and respiratory compensation to keep up. This distinction is the single most common conceptual error in the topic, and it explains why lactate infusion studies do not reproduce the hemodynamic collapse of true lactic acidosis.

Lactate exists as two stereoisomers. L-lactate is the form made by human and animal LDH and the form measured by essentially all clinical analyzers. D-lactate is produced by bacterial fermentation in the gut and rumen and is not detected by standard L-lactate assays, which is why D-lactic acidosis can be missed on routine testing [3][4].

The Lactate Dehydrogenase Reaction

The core reaction is a single, reversible, NAD-dependent redox step:

Pyruvate + NADH + H+ ⇌ L-lactate + NAD+

LDH catalyzes this in both directions. The direction that dominates in a given cell depends on the local ratio of NADH to NAD+ (the redox state) and on the concentration of pyruvate. When glycolysis outruns mitochondrial pyruvate oxidation, NADH accumulates, the NADH/NAD+ ratio rises, and the equilibrium is pushed toward lactate. This regenerates NAD+, which is the rate-limiting cofactor for the glyceraldehyde-3-phosphate dehydrogenase step of glycolysis. Without that regeneration, glycolysis would stall within seconds.

LDH is a tetramer assembled from two subunit types, M (muscle, LDHA) and H (heart, LDHB), giving five isoenzymes. LDHA-rich isoenzymes (LDH-4 and LDH-5) favor pyruvate reduction and are found in skeletal muscle, liver, and tumors. LDHB-rich isoenzymes (LDH-1 and LDH-2) favor lactate oxidation and dominate in cardiac muscle, which is why the heart is a net lactate consumer rather than a producer. Elevated circulating LDHA in skeletal muscle raises circulating lactate and correlates with hyperglycemia in both mouse models and human subjects, and muscle-specific deletion of Ldha paradoxically worsens glucose homeostasis by driving hepatic gluconeogenesis [2].

Lactate produced by this reaction is not a dead end. It is a substrate for three fates: oxidation back to pyruvate in mitochondria, conversion to glucose in the liver and kidney cortex, or use as a signaling molecule through lactylation and the G-protein-coupled receptor GPR81 [1][5].

How Lactate Is Produced: Step by Step

Glucose enters the cell and is phosphorylated to glucose-6-phosphate by hexokinase.
Glycolysis proceeds through ten enzymatic steps to pyruvate, generating 2 ATP and 2 NADH per glucose.
Pyruvate has two possible fates. It can enter the mitochondrion and be converted to acetyl-CoA by pyruvate dehydrogenase (PDH), feeding the TCA cycle and oxidative phosphorylation, or it can stay in the cytosol.
When oxygen delivery is limiting, or when PDH is inhibited, or when glycolytic flux simply exceeds mitochondrial capacity, pyruvate accumulates in the cytosol.
LDH reduces that pyruvate to lactate using NADH, regenerating NAD+ and allowing glycolysis to continue.
Lactate exits the cell through monocarboxylate transporters (MCT1 and MCT4) and enters the bloodstream.
Lactate is taken up by oxidative tissues (heart, slow-twitch muscle, liver, kidney, brain) through MCT1 and either oxidized or converted back to glucose.

The key point is that lactate production is not a sign of failure. It is a redox-balancing strategy that lets a cell keep making ATP when mitochondrial flux is constrained. In yaks adapted to high altitude, chronic hypoxia increases skeletal muscle lactate and AARS2 expression while decreasing PDHA1 and CPT2, and protein lactylation rises in parallel, showing that this shift is a regulated, tissue-level adaptation rather than a passive overflow [6].

The Lactate Shuttle and the Cori Cycle

Intracellular and Intercellular Shuttles

The lactate shuttle describes the movement of lactate between producer and consumer compartments. Three scales exist:

Intracellular: lactate made in the cytosol is transported into the mitochondrion and oxidized there, a route that keeps lactate within the same cell.
Intercellular: fast-twitch glycolytic fibers produce lactate, and adjacent slow-twitch oxidative fibers take it up and oxidize it. This is the classic explanation for why type I fibers stain less intensely for glycogen but have high mitochondrial density.
Intertissue: lactate released into blood is extracted by heart, liver, kidney, and brain.

The shuttle is regulated by MCT isoform expression, PGC-1α, calcium signaling, and histone lactylation, and it directly influences skeletal muscle fiber type transitions [1]. This means lactate is a signaling molecule that helps determine what kind of muscle a fiber becomes, not just a waste product to be cleared.

The Cori Cycle

The Cori cycle is the interorgan loop that returns muscle lactate to glucose:

Skeletal muscle performs anaerobic glycolysis and releases lactate into the blood.
The liver (and, to a lesser extent, the kidney cortex) extracts lactate via MCT1.
Hepatic LDH converts lactate back to pyruvate.
Pyruvate enters gluconeogenesis, consuming 6 ATP equivalents per glucose molecule produced.
The newly made glucose is released into the blood and taken up again by muscle.

The Cori cycle is energetically expensive. It shifts the metabolic cost of clearing muscle lactate onto the liver, which is why hepatic function is a rate-limiting factor in whole-body lactate tolerance. In aged mice, impaired liver lactate processing causes lactate accumulation and intracellular acidification in skeletal muscle, and this lactic acidosis is a driver of sarcopenia. Pharmacological HIF activation in the liver restores lactate tolerance and improves muscle function, and the mechanism runs through a fall in muscle NAD+ [7].

The Heart as a Lactate Consumer

Cardiac muscle is the body's most lactate-hungry tissue per gram. It expresses LDHB-rich isoenzymes and MCT1, extracts lactate from arterial blood in proportion to its concentration, and oxidizes it in preference to glucose and free fatty acids when lactate is abundant. This is why a heart that is failing to perfuse itself is doubly disadvantaged: it loses its preferred fuel and it accumulates the protons that impair contractility. In an experimental model of extracellular lactic acidosis (22 mM lactic acid, pH 6.9), ventricular strips from a fast-swimming Amazonian fish showed an initial drop in contractile force followed by complete recovery, and that recovery depended on sarcoplasmic reticulum calcium release and the Na+/H+ exchanger [8]. The general principle holds across vertebrates: lactic acidosis depresses myocardial contractility, and the ability to recover depends on pH regulatory machinery.

Normal Blood Lactate Values

Blood lactate is reported in millimoles per liter (mmol/L). The values below reflect the consensus range for resting, well-perfused, non-exercising subjects. Reference intervals vary slightly by analyzer and by whether the sample is arterial, venous, or capillary, so each laboratory's own interval should be used for clinical decisions.

Species	Typical resting blood L-lactate (mmol/L)	Notes
Human	0.5 to 2.2	Arterial slightly lower than venous
Dog	0.5 to 2.5	Venous samples common in practice
Cat	0.5 to 2.5	Values rise with stress and struggling
Horse	0.5 to 1.5 at rest	Rises sharply with sprint exercise
Cow	0.5 to 1.5	D-lactate must be measured separately in ruminal acidosis

The threshold most commonly used to define hyperlactatemia is a blood lactate above 2.0 mmol/L, with values above 4.0 mmol/L generally considered marked and values above 5.0 mmol/L part of the diagnostic picture for lactic acidosis when accompanied by metabolic acidosis [9]. Metformin-associated lactic acidosis, for example, is defined by lactate above 5 mmol/L, arterial pH below 7.35, and a high anion gap [9]. Note that lactate can be elevated with normal acid-base status, and acidosis can be present with only modest lactate elevation, so the two must be interpreted together.

Sample handling matters. Lactate in a plain tube rises over time as red cells continue glycolysis, so samples should be analyzed promptly or collected in a tube containing sodium fluoride to inhibit glycolysis. Tourniquet time, fist clenching, and struggling during venipuncture all raise measured lactate independent of any disease process.

Type A Versus Type B Lactic Acidosis

Lactic acidosis is defined by an elevated blood lactate together with a low arterial pH (acidemia) and a high anion gap. The traditional classification splits causes into two groups.

Type A is lactic acidosis attributable to tissue hypoxia or hypoperfusion. Oxygen delivery falls short of demand, mitochondria cannot oxidize pyruvate, and lactate accumulates. Causes include shock of any kind (hypovolemic, cardiogenic, distributive), regional ischemia such as mesenteric infarction, severe anemia, carbon monoxide poisoning, prolonged seizures, and intense exercise beyond the anaerobic threshold.

Type B is lactic acidosis without clinical evidence of tissue hypoxia. The mechanism is either increased production, decreased clearance, or both. Type B is subdivided into three categories: underlying disease, drugs and toxins, and inborn errors of metabolism [3].

Type	Mechanism	Representative causes
A	Tissue hypoxia or hypoperfusion	Shock, sepsis with hypoperfusion, cardiac arrest, mesenteric ischemia, severe anemia, carbon monoxide, status epilepticus, exhaustive exercise
B1	Underlying disease, no hypoxia	Liver failure, renal failure, diabetic ketoacidosis, malignancy (leukemia, lymphoma), thiamine deficiency, HIV
B2	Drugs and toxins	Metformin, nucleoside reverse transcriptase inhibitors, linezolid, salicylates, cyanide, ethanol, propofol, catecholamines
B3	Inborn errors of metabolism	Mitochondrial disease including MELAS, pyruvate dehydrogenase deficiency, glycogen storage diseases, organic acidemias
D-lactate	Bacterial fermentation	Short bowel syndrome, ruminal acidosis in cattle and sheep, jejunoileal bypass

Type B is easy to miss because the clinician's reflex is to look for shock. Metformin-associated lactic acidosis is the archetype: it is fundamentally an accumulation disorder driven by declining kidney function, not intrinsic drug toxicity at therapeutic concentrations. Metformin inhibits mitochondrial complex I, alters the intracellular redox state, and reduces hepatic lactate clearance, and the precipitating event is usually acute kidney injury, chronic kidney disease progression, hepatic impairment, sepsis, hypoxia, or dehydration [9][10].

Malignancy causes type B through the Warburg effect. Aggressive tumors such as Burkitt lymphoma consume glucose at very high rates and produce lactate even in the presence of adequate oxygen, and the resulting lactic acidosis can be severe and resistant to supportive care until the tumor burden is reduced [11]. In tuberculosis, a similar glycolytic switch in infected macrophages, governed by HIF-1α, contributes to systemic lactate elevation and to muscle wasting through cytokine and metabolite circuits [12].

Mitochondrial disease is the classic type B3 cause. MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is most often caused by the m.3243A>G variant in mitochondrial tRNA-Leu, and lactate elevation is a core diagnostic feature [13]. Patient-derived brain organoid models show that phenotype severity tracks with heteroplasmy level, which is why lactate can be normal in some carriers and markedly elevated in others [13].

D-lactic acidosis deserves separate mention because standard assays miss it. In ruminants, acute ruminal acidosis after a sudden concentrate meal produces ruminal pH below 5.0 and elevated plasma L- and D-lactic acid, along with free lipopolysaccharide, and both contribute to systemic inflammation [4]. In humans, D-lactic acidosis occurs after jejunoileal bypass or in short bowel syndrome when colonic bacteria ferment carbohydrate to D-lactate faster than the body can metabolize it [3].

How Lactate Is Measured in Practice

Blood lactate is measured by one of three methods:

Enzymatic amperometric analyzers. Most point-of-care and benchtop blood gas analyzers use an LDH-based biosensor that oxidizes L-lactate and measures the resulting current. Sample volume is typically 100 to 200 microliters of whole blood, and turnaround is under two minutes.
Spectrophotometric assays. LDH converts lactate to pyruvate, and the NADH generated is measured at 340 nm. These are common in research and in veterinary reference laboratories.
Nuclear magnetic resonance and mass spectrometry. Used for research-grade quantification of lactate and its isotopomers, and for tracing labeled carbon through the Cori cycle.

Two practical points. First, D-lactate requires a separate assay, so a normal L-lactate does not exclude D-lactic acidosis [3]. Second, lactate is a dynamic variable. A single value is less informative than a trend, and in trauma patients with midrange injury severity, base excess and lactate are often only borderline deranged, which is why investigators have looked at neutrophil phenotypes as an alternative severity marker [14].

The Muscle Soreness Myth

Delayed onset muscle soreness (DOMS) peaks 24 to 72 hours after unaccustomed exercise. Lactate is cleared from blood within roughly an hour of exercise cessation, so it cannot be the cause of soreness that appears a day later. The actual drivers of DOMS are mechanical disruption of sarcomeres, especially at the Z-discs, plus the subsequent inflammatory response and edema in the affected muscle.

The "burn" felt during intense exercise is a different phenomenon and is largely attributable to proton accumulation lowering intramuscular pH, not to lactate itself. Lactate is actually a fuel. It is extracted from blood by heart, liver, and oxidative skeletal muscle and oxidized through the TCA cycle, and it is the preferred substrate for cardiac muscle under many conditions. Lactate also feeds gluconeogenesis through the Cori cycle. Calling lactate a waste product is wrong on both counts.

Lactate does have real biological effects, but they are regulatory rather than toxic. It modifies lysine residues on histones and on metabolic enzymes, a mark called lactylation, and it signals through GPR81. In skeletal muscle, GPR81 activation improves lipid oxidation and reduces lipid accumulation, and GPR81 agonists improve muscle regeneration in progeroid mice [5]. In the liver, muscle-derived lactate acts as a negative feedback signal on hepatic gluconeogenesis via H3K18 lactylation and IL-6 [2]. In yaks under chronic hypoxia, PDHA1 and CPT2 are themselves lactylated, linking lactate directly to the regulation of pyruvate entry into mitochondria and fatty acid transport [6].

Quick Review

Lactic acid is the protonated form. At physiological pH, the molecule is lactate plus a free proton, and the proton is what lowers pH.
LDH catalyzes pyruvate + NADH + H+ lactate + NAD+, regenerating NAD+ so glycolysis can continue.
Normal resting blood lactate is roughly 0.5 to 2.2 mmol/L in humans and similar in dogs and cats, with horses and cattle at the lower end at rest.
Hyperlactatemia is generally defined as blood lactate above 2.0 mmol/L, and lactic acidosis requires lactate elevation plus acidemia.
Type A lactic acidosis is hypoxic or hypoperfusion-driven. Type B is everything else, including metformin, liver failure, seizures, malignancy, and mitochondrial disease.
The Cori cycle returns muscle lactate to the liver for gluconeogenesis, and the heart consumes lactate as a preferred fuel.
Lactate does not cause DOMS. It is a fuel and a signaling molecule.

Common Mistakes and Limitations

Confusing lactate with acid load. Lactate is a base at physiological pH. The acid load comes from the proton released during the LDH reaction and from ATP hydrolysis. A patient can have a high lactate with a normal pH if buffering and respiratory compensation are adequate, and a patient can be acidemic with a modest lactate if another acid is responsible.

Assuming any elevated lactate means shock. Type B causes are common and are missed when the clinician stops at "hypoperfusion." Metformin, liver failure, seizures, hematologic malignancy, and mitochondrial disease all raise lactate without tissue hypoxia [3][9][11].

Forgetting D-lactate. Standard assays measure only L-lactate. Short bowel syndrome, jejunoileal bypass, and ruminal acidosis in cattle and sheep can produce significant D-lactate that a routine panel will not detect [3][4].

Ignoring clearance. Lactate is a balance between production and clearance. Liver failure and renal failure raise lactate by reducing clearance even when production is normal. This is why metformin-associated lactic acidosis is best understood as an accumulation disorder triggered by declining kidney function [9][10].

Treating a single value as definitive. Lactate is dynamic. Sample handling, tourniquet time, struggling, and delay before analysis all shift the number. Trends over time carry more information than any single measurement.

Overgeneralizing from animal models. Much of the mechanistic work on lactate shuttling, lactylation, and sarcopenia comes from mice, yaks, pigs, and fish [6][7][15][8]. The pathways are conserved, but exact thresholds and kinetics differ across species, and veterinary reference intervals should always come from the laboratory that ran the sample.

Individual cases need a veterinarian. A lactate value in a sick dog, cat, horse, or cow must be interpreted alongside the physical exam, perfusion parameters, acid-base status, and the animal's own history.

flowchart TD
    A[Glucose] --> B[Glycolysis]
    B --> C[Pyruvate]
    C --> D{Oxygen and mitochondria adequate}
    D -->|Yes| E[Acetyl CoA]
    E --> F[TCA cycle and oxidative phosphorylation]
    D -->|No| G[Lactate dehydrogenase]
    G --> H[Lactate plus proton]
    H --> I[Monocarboxylate transporters]
    I --> J[Blood lactate]
    J --> K[Heart oxidation]
    J --> L[Liver gluconeogenesis]
    L --> A

Frequently Asked Questions

What is lactic acid?

Lactic acid is the protonated form of lactate, a three-carbon molecule produced when pyruvate is reduced by lactate dehydrogenase during glycolysis. At blood pH, almost all of it exists as lactate plus a free proton, so the two names describe the same metabolic endpoint under different chemical conditions.

What is lactic acidosis?

Lactic acidosis is the combination of elevated blood lactate with acidemia and a high anion gap. The acidosis comes from proton release during lactate production and from impaired buffering, not from lactate itself, and it is classified as type A when tissue hypoxia or hypoperfusion is present and type B when it is not.

What causes lactic acid build-up?

Lactic acid build-up occurs when production exceeds clearance. Causes include shock and hypoperfusion, intense exercise, seizures, liver failure, renal failure, metformin and other drugs, thiamine deficiency, aggressive malignancies, mitochondrial disease, and bacterial D-lactate production in the gut or rumen.

What is a normal lactate level?

Normal resting blood lactate is approximately 0.5 to 2.2 mmol/L in humans, 0.5 to 2.5 mmol/L in dogs and cats, and 0.5 to 1.5 mmol/L in horses and cattle at rest. Hyperlactatemia is generally defined as a value above 2.0 mmol/L, and values above 4 to 5 mmol/L are considered marked.

Does lactic acid cause muscle soreness?

No. Lactate clears from blood within about an hour of exercise, while delayed onset muscle soreness peaks 24 to 72 hours later. Soreness comes from mechanical sarcomere damage and the subsequent inflammatory response, and the burning sensation during exercise comes mainly from proton accumulation.

Is lactate a waste product?

No. Lactate is a circulating fuel that the heart, liver, kidney, and oxidative skeletal muscle extract and oxidize, and it is a substrate for hepatic gluconeogenesis through the Cori cycle. It also acts as a signaling molecule through histone and enzyme lactylation and through the receptor GPR81.