Physiology Friday #233: Exercise Makes Us More Stress-Resilient: Now We Know Why
Lactate as a brain fuel. It's so en vogue.
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If you watched any of the running, swimming, or cycling events at this year’s Olympic Games, it’s likely you heard one of the commentators (errantly) remark about how the athletes, in the final and highest-intensity stage of the race, had gone “full lactic!”
They were, of course, referring to lactic acid — the once-thought-toxic byproduct of intense exercise that explains the burn you feel when pushing yourself to the limit. Lactic acid was viewed for decades as the reason behind muscle fatigue, and athletes did everything they could to “flush it out” of their bodies after exercise. That burn you feel in your muscles during an all-out sprint? Blame lactate.
Everyone from coaches to physiology textbooks proclaimed lactic acid as a metabolic poison. Just one problem: it’s not.
For one, humans don’t even produce lactic acid, but rather, lactate, during aerobic and anaerobic metabolism. I’ll spare you the biochemistry lesson.
Second, lactate is not a metabolic waste product or the cause of muscle fatigue. Rather, it’s an intermediary and an energy source in the complex dance of metabolism. Our body continuously forms and releases lactate from skeletal muscle, skin, and red blood cells — this lactate can be shuttled from cell to cell and serve as a source of energy in oxidative tissues like the heart. Lactate is also produced in the brain during neuronal activity.
Lactate can also be used to produce glucose in the liver and kidneys. This complex coordination of lactate metabolism happens at rest, after we eat, and during exercise (both aerobic and anaerobic).
In addition to its role in metabolism, lactate is recognized as a crucial signaling molecule — an exerkine and a myokine — with roles in brain, heart, and muscle health.
One of the key roles of lactate in the brain is to increase brain-derived neurotrophic factor or BDNF — a growth factor that acts on neurons in the central and peripheral nervous system. Colloquially referred to as “Miracle-Gro for the brain,” BDNF promotes neurogenesis — the growth of new neurons — to enhance learning, long-term memory, and executive function. It’s been suggested that lactate, via its effects on BDNF, likely mediates some of exercise’s benefits on cognitive function.
According to a new study, lactate might also explain why exercise makes us more resilient to stress.1
Exercise has well-known anxiety-reducing effects and protects against cognitive decline and neurodegenerative diseases. It promotes psychological and physiological resilience in the brain. These benefits have commonly been attributed to improvements in metabolism or reductions in inflammation. Several neurotransmitters and metabolites like ketone bodies, kynurenine, and dopamine, among other molecules, have been proposed as being culpable.
But exercise may also confer stress-resilience-enhancing effects via non-metabolic pathways, enlisting lactate to do so.
Indeed, lactate — in addition to its role as an energy source — is a signaling molecule that can participate in the epigenetic modification of proteins. This is known as lactylation. When lactate modifies a protein or amino acid residue, that protein becomes lactylated. This epigenetic change then causes a cascade of events that can lead to gene expression, protein expression, and downstream adaptations in the brain and body.
Could lactylation explain the stress-enhancing effects of exercise?
To test this hypothesis, researchers subjected a group of mice to 14 days of treadmill exercise training. The mice ran for one hour per day. Another group of mice (the control group) didn’t do any training.
The mice didn’t just train during these 14 days — they were also subjected to an experimental protocol that causes stress and anxiety, what researchers refer to as chronic restraint stress or the CRS model. The CRS model reliably causes anxiety-like behaviors in rodents; it’s akin to putting you in a very small room where your physical activity and movement are incredibly limited. Enough to make anyone anxious and depressed after just a few hours.
During the experiment, the mice who exercised didn’t display the anxiety-like behaviors that the untrained mice did. This supports the anxiety-reducing effects of exercise.
These mice also had higher lactate levels in their liver, muscle tissues, and brain, specifically in the medial prefrontal cortex or mPFC. It wasn’t just lactate that was higher in the brains of the exercise-trained mice either, so were the enzymes lactate dehydrogenase A/B, which are involved in lactate biosynthesis. In other words, these mice could produce more lactate after exercise training and use that lactate more efficiently.
To show that the anxiety-reducing effects of lactate were actually due to lactate (and not some other off-target effect of exercise), the researchers did something innovative. Instead of subjecting the mice to exercise training and chronic restraint stress, they exposed them to stress but injected them with lactate instead of exercise. This was enough to attenuate the anxiety-like behaviors during stress. Furthermore, when the researchers gave the exercise-trained mice something that inhibited lactate production, exercise did not affect their anxiety-like behaviors.
All of this is to say that lactate is necessary for exercise to prevent anxiety and stress resilience, at least in this experimental model.
Not surprisingly, the higher the intensity of exercise, the higher the levels of brain lactate, although there did appear to be a saturation point — mice who ran at 15 meters per minute (0.55 miles per hour) didn’t have higher lactate levels than mice who ran 10 meters per minute (0.37 miles per hour), though both of these speeds resulted in higher lactate levels than 5 meters per minute (0.18 miles per hour).
Higher-intensity exercise also produced a more robust reduction in anxiety compared to lower-intensity treadmill running, supporting the idea that high-intensity exercise has greater cognitive benefits than moderate-intensity exercise.
The effects of lactate appeared to be driven by the lactylation of one particular synaptic protein known as SNAP91. Mice exposed to stress who didn’t exercise had lower levels of SNAP91 lactylation, while the mice who exercised had elevated SNAP91 lactylation.
What exactly does SNAP91 do? And how does this relate to stress resilience?
A complex set of experiments indicated that SNAP91 improves pre- and post-synaptic structures in the brain, which likely allows for better regulation of neurotransmitter release and neuron excitability during stress. As evidence to support this, mice with a mutation in SNAP91 (resulting in down-regulated lactylation of this protein) had reduced neural function and displayed anxiety-like behaviors during several behavioral stress tests. Even when these mutant mice performed exercise training, they still displayed anxious behaviors. Exercise doesn’t protect against stress unless lactylation is allowed to happen!
Importantly, this only seemed to occur in the mPFC but not the hippocampus or the amygdala — other brain regions implicated in anxiety disorders.
This finding implicated lactylation of SNAP91 in the medial prefrontal cortex as the primary site of exercise (and lactate’s) anxiolytic effects, which appear to “reshape the homeostasis of synaptic protein lactylation, counteracting [stress] and preventing anxiety-like behaviors.”
Not only has lactate been vindicated in recent decades, but it’s also gained notoriety as something essential for physiological function — the body loves lactate as a fuel source.
As this study suggests, chronic exposure to elevated levels of lactate, and the use of lactate as a metabolic fuel, probably confer long-term beneficial adaptations throughout the body and the brain, one of which is resilience against psychological stress.
This probably comes as no surprise to any of you who engage in regular exercise. It fundamentally changes our neurological structure and function. We become less anxious, less depressed, more “chill”, and less prone to overreacting to mundane stresses in life — we also become better at dealing with stress when it does come our way; that’s the essence of stress resilience.
Do these findings explain why exercise confers protection against psychological disorders, cognitive decline, and Alzheimer’s disease? Perhaps. We know that all of these conditions have a metabolic component, and thus probably benefit from crosstalk within the metabolism-brain axis through which lactate mediates its effects.
The clear limitation of this study (for readers of this post at least) is that it was conducted on mice, not humans. But I don’t think this is a reason to dismiss the findings — discovering important mechanistic pathways often first requires this type of work. Let’s hope translation into larger studies in people follows!
The next time you’re feeling the gratifying burn of a high-intensity run or an intense lift in the gym, think not of the improvements in VO2 max or hypertrophy that will inevitably ensue. Rather, picture lactate — our body’s metabolic master fuel — strengthening your neurons and changing your brain.
If exercise has made you psychologically stronger, happier, or more mentally sharp, you probably have lactate to thank.
Thanks for reading. See you next Friday.
~Brady~
The VO2 Max Essentials eBook is your comprehensive guide to aerobic fitness, how to improve it, and its importance for health, performance, and longevity. Get your copy today and use code SUBSTACK20 at checkout for a 20% discount. You can also grab the Kindle eBook, paperback, or hardcover version on Amazon.
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FSTFUEL combines electrolytes with amino acids to help your body maintain hydration and optimal functioning during exercise or intermittent fasting, so you don't have to choose between fasting and fitness. If you want to try some, the guys at FSTFUEL have agreed to give my audience a 30% discount on their orders. Just use the coupon code BRADY30 at checkout.