#312 - A masterclass in lactate: Its critical role as metabolic fuel, implications for diseases, and therapeutic potential from cancer to brain health and beyond | George A. Brooks, Ph.D.
George Brooks, UC Berkeley Professor, discusses his groundbreaking "lactate shuttle" theory, clarifying lactate's role as a crucial fuel source. He explores its significance in metabolism, athletic performance, type 2 diabetes, cancer, and brain injuries.
Deep Dive Analysis
13 Topic Outline
Introduction to Lactate Misconceptions and George Brooks' Work
Historical Understanding of Lactic Acid and Meyerhoff's Experiment
Fundamentals of Glucose Metabolism and ATP Production
Lactate as a Preferred Mitochondrial Fuel and Substrate Competition
Lactate's Role in Traumatic Brain Injury (TBI) Treatment
Lactate's Influence on Appetite Regulation
Metabolic Differences: Athletes vs. Insulin-Resistant Individuals
MCTs and Lactate Shuttling Between Muscle Fiber Types
Lactate's Role in Cancer and Exercise Benefits
Lactate in Sepsis and the Significance of D-Lactate
Enteric Glycolysis and Lactate Production from Oral Glucose
Lactate's Influence on Gene Expression (Lactylation)
Future Research Directions and Unanswered Questions
5 Key Concepts
Lactate Shuttle Theory
Proposed by George Brooks, this theory posits that lactate is a crucial fuel source for muscles and other cells, actively produced and utilized, rather than merely an unfortunate byproduct of anaerobic metabolism. It highlights lactate's role in energy distribution and utilization throughout the body.
Monocarboxylate Transporters (MCTs)
These are proteins responsible for transporting monocarboxylates, including lactate and ketones, across cell membranes. Crucially, MCTs are found not only on the cell surface for export but also on mitochondrial membranes, facilitating lactate's entry into mitochondria for oxidation.
Cell-Cell Lactate Shuttle
This describes the process where fast glycolytic (Type 2) muscle fibers produce lactate and shuttle it to adjacent slow oxidative (Type 1) muscle fibers for consumption and oxidation. This allows efficient local utilization of lactate within muscle tissue, reducing its appearance in venous blood.
Warburg Effect
This phenomenon describes how cancer cells preferentially metabolize glucose to lactate, even in the presence of ample oxygen. While initially thought to indicate defective mitochondria, it's now understood that this metabolic pathway may be optimized for providing cellular building blocks for rapid replication, rather than just ATP efficiency.
Lactylation
A newly recognized epigenetic modification where lactate can directly and covalently bind to histones, similar to acetylation or methylation. This binding can influence gene expression, suggesting lactate acts as a potent signaling molecule beyond its metabolic role.
11 Questions Answered
The body primarily produces lactate, which is an anion, not lactic acid. Lactic acid is formed when lactate is associated with a hydrogen ion, but the final step of glycolysis, which produces lactate, is actually an alkalizing step.
Early 20th-century experiments, like Meyerhoff's with frog muscles in anaerobic conditions, observed lactate accumulation alongside acidosis and muscle fatigue. This led to the incorrect association of lactate with oxygen lack, acidosis, and fatigue.
Glucose enters cells via specific glucose transporters (e.g., GLUT4 in muscle and fat, activated by insulin or contraction). Once inside, it can either be stored as glycogen or enter the glycolytic pathway to be degraded for energy, primarily producing lactate.
Yes, lactate is transported into mitochondria via monocarboxylate transporters (MCTs) and is a preferred fuel for oxidative phosphorylation, where it is converted to pyruvate and then oxidized to generate ATP.
Lactate metabolism generates acetyl-CoA, which inhibits the enzymes (CPT1 and CPT2) responsible for transporting fatty acids into mitochondria for oxidation. This prioritizes fast-acting carbohydrate fuel during high-demand, sympathetic states.
In an injured brain, glucose uptake can be impaired, leading to a metabolic crisis. Lactate, which can be transported into brain cells via MCTs, can serve as a preferred and vital fuel for neurons, potentially aiding in recovery from TBI.
Exercise training increases mitochondrial mass and the abundance of MCTs in muscle cells. This enhances the capacity to produce lactate, shuttle it between muscle fibers, and efficiently oxidize it within mitochondria or transport it to other tissues like the liver for gluconeogenesis.
Elevated lactate levels, such as those achieved during moderate to intense exercise, can cross the blood-brain barrier and act on the hypothalamus to inhibit ghrelin secretion, thereby suppressing appetite and promoting satiety.
Elevated lactate is a marker in sepsis, but common assays primarily measure L-lactate (the form the body typically produces). Microbes in the gut can produce D-lactate, which is neurotoxic and pro-inflammatory, and its presence might be a more significant, yet often unmeasured, contributor to sepsis pathophysiology.
Following an oral glucose tolerance test, lactate levels in arterial blood spike rapidly (within 5-15 minutes), often before glucose levels peak. This initial lactate production is primarily due to enteric glycolysis in enterocytes, which convert glucose to lactate for energy distribution.
Yes, lactate can act as a signaling molecule by directly binding to histones, a process known as lactylation. This epigenetic modification can affect gene expression, potentially playing a role in cellular adaptations like mitochondrial biogenesis.
15 Actionable Insights
1. Double Mitochondrial Mass via Training
Engage in consistent training over several weeks to months, as this can double mitochondrial mass in muscle, enhancing the body’s energy delivery system and improving metabolic capacity.
2. Exercise to Suppress Appetite
Engage in exercise intense enough to raise lactate levels to around 3-4 millimolar, as this can cross the blood-brain barrier, inhibit ghrelin secretion, and suppress appetite for several hours post-exercise.
3. Increase MCT Density with Training
Train consistently to increase the abundance of monocarboxylate transporters (MCTs) in muscle cells, which facilitates both the export of lactate and its uptake into mitochondria for oxidation.
4. Enhance Lactate Clearance for Cancer
Increase your body’s lactate clearance capacity through regular exercise, as effective removal of lactate may lessen the chance for carcinogenesis if lactate is indeed carcinogenic.
5. Generate Endogenous Lactate for Biogenesis
To stimulate mitochondrial biogenesis, focus on generating high levels of endogenous lactate through exercise, as this appears to be a more effective signal than simply infusing exogenous lactate.
6. Exercise for Brain Health, Neurogenesis
Engage in physical exercise to promote brain health, as it can stimulate neurogenesis in the dentate gyrus and improve brain blood flow and substrate delivery, contributing to the development of new brain cells.
7. Exercise Boosts Cognition
Engage in exercise that raises lactate levels, as this can temporarily improve scores on cognitive tests and fuel the brain, suggesting a direct link between physical activity and enhanced executive function.
8. Administer Lactate for TBI
For brain-injured individuals, consider intravenous lactate infusion, as early clinical trials suggest it may serve as a preferred fuel source for injured neurons and could lead to better outcomes.
9. Use ‘Lactate,’ Not ‘Lactic Acid’
Refer to the molecule as ’lactate’ rather than ’lactic acid,’ as the body produces lactate, and this distinction corrects a century-old historical mistake in understanding its role.
10. Recognize Lactate as Fuel
Understand that lactate is an integral participant in powering muscle and all cells, serving as a crucial fuel source rather than merely an unfortunate byproduct or waste product of exercise.
11. Metformin’s Lactate: A Good Thing
If taking metformin, understand that the associated rise in lactate levels may be a beneficial outcome, as the drug could be encouraging enterocytes to produce lactate as a valuable carbohydrate energy form.
12. Distinguish Lactate from pH in Sepsis
In septic patients, differentiate between elevated lactate and low pH; while a low pH requires intervention, a high lactate level in the absence of a significant pH change may not warrant aggressive treatment for acidosis.
13. Recognize Enteric Glycolysis
Understand that enteric glycolysis, occurring in the gut, is an initial and rapid process of carbohydrate energy distribution, producing lactate that appears in arterial blood even before glucose levels significantly rise after a meal.
14. Liver Sequestering Glucose Load
Understand that the liver plays a key role in glucose disposal, sequestering approximately 80% of an oral glucose load and gradually releasing it over time, rather than immediate muscle uptake.
15. Lactate Signals Gene Expression
Recognize that lactate is a potent signaling molecule that can directly bind to genes (lactylation) and affect gene expression, potentially influencing mitochondrial biogenesis and other physiological adaptations.
6 Key Quotes
The body does not make lactic acid. It makes lactate.
George Brooks
We've been teaching glycolysis wrong for a hundred years.
George Brooks
Lactate basically shuts the door, blocks fatty acid metabolism.
George Brooks
Lactate is a preferred fuel over glucose in the brain and muscle, wherever.
George Brooks
Lactate is there to moderate. It's a strain response. It's helping to protect you.
George Brooks
If you just take muscles, put them in a muscle cells in a dish, you had lactate, you activate 500 genes.
George Brooks