Original episode & show notes | Raw transcript
For years, a popular hypothesis in endurance sports has been that training with low muscle glycogen stores—often called “training low”—could be a shortcut to superior aerobic adaptations. The central idea is that exercising in a glycogen-depleted state creates a significant cellular stress, which in turn amplifies the molecular signals that drive improvements in endurance, such as the creation of new mitochondria (mitochondrial biogenesis).
This document unpacks the science behind this hypothesis, focusing on a key signaling pathway known as p38 mitogen-activated protein kinase (MAPK). We will examine the foundational research, critique the human performance studies, and ultimately arrive at an evidence-based conclusion about the efficacy of this training strategy, as detailed in the provided podcast.
To understand the debate, we must first understand the key molecular players involved in how our muscles adapt to exercise.
What is it? p38 MAPK is a type of protein known as a kinase, which means its job is to add phosphate groups to other proteins, thereby activating or deactivating them. It is a central component of a signaling pathway that responds to a wide variety of cellular stressors, including osmotic shock, inflammatory cytokines, and, most importantly for our purposes, the stress induced by exercise.
Role in Muscle: In skeletal muscle, the p38 MAPK pathway is a crucial mediator of adaptation. Its activation has been linked to several positive outcomes.
Beyond Exercise: It’s important to note that p38 MAPK is not exclusive to exercise adaptation. It plays a fundamental role in many tissues. For instance, it is heavily involved in cell differentiation (the process by which a stem cell becomes a specialized cell) and mitosis (cell division). In muscle, it helps govern the differentiation of satellite cells (muscle stem cells) to repair and grow muscle fibers. Its role in cell proliferation also makes it a major area of study in cancer research, where mutations in pathways involving p38 can lead to uncontrolled cell growth.
What is it? Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) is often called the “master regulator” of mitochondrial biogenesis. It is a protein that, when activated, coordinates the expression of a large number of genes required to build new mitochondria.
Why it Matters: More mitochondria mean a greater capacity for aerobic metabolism—the ability to produce energy (ATP) using oxygen. This is the cornerstone of endurance performance. Therefore, any training stimulus that effectively increases the activity of PGC-1α is highly sought after.
The “train low” hypothesis hinges on the idea that low glycogen potentiates p38 MAPK activity, which in turn drives PGC-1α and enhances adaptation. Let’s follow the scientific trail.
A highly-cited 2005 paper by Akimoto and colleagues provided the foundational evidence linking p38 MAPK to PGC-1α.
Correlation in Mice: Researchers had mice perform a bout of exercise and observed that the activation of p38 (measured by its phosphorylation) occurred over the same time frame as the increase in PGC-1α gene expression (mRNA). This established a correlation.
Proving Causation in a Dish: To prove causation, they used cultured muscle precursor cells (myoblasts).
They introduced a luciferase reporter gene attached to the PGC-1α gene. Luciferase is a protein that glows (like in fireflies); if the PGC-1α gene was being transcribed, the cells would glow, providing a direct measure of its activity.
When they added a chemical that activates the p38 pathway, the cells glowed brightly, indicating high PGC-1α transcription.
Crucially, when they added both the p38 activator and a p38 inhibitor, the glow disappeared. This demonstrated that p38 MAPK activation is necessary for PGC-1α transcription.
Confirmation in Living Muscle: Finally, they created transgenic mice whose muscles had a constantly active p38-stimulating protein. These mice showed a large increase in PGC-1α protein and other mitochondrial markers, confirming that this pathway works in living tissue.
Conclusion from Akimoto: The p38 MAPK pathway is a direct and potent activator of PGC-1α and mitochondrial biogenesis. This makes it a plausible mechanism for the “train low” hypothesis.
With the pathway established, the next step was to see if low glycogen actually potentiated this signal in humans and led to better performance. A key study investigated this using a clever protocol.
The Setup: Two groups of matched athletes trained for three weeks.
Group 1 (Normal Glycogen): Performed high-intensity intervals (8x5 min max efforts) on one day and a long endurance ride (100 min at ~70% VO₂max) on the next, with a rest day in between. They started every session with normal glycogen.
Group 2 (Low Glycogen): Performed the long endurance ride immediately followed by the high-intensity intervals on the same day, with a one-hour rest between. This ensured they started the high-intensity work with significantly depleted muscle glycogen.
The Molecular Results:
AMPK: Activation of AMPK (another energy sensor) was 40% higher in the low-glycogen group. This makes sense, as the cells were under greater energy stress.
p38 MAPK: There was NO DIFFERENCE in the activation of p38 MAPK between the two groups. The central tenet of the “train low” hypothesis—that low glycogen would potentiate this specific signal—was not supported.
The Performance Results:
Interval Power: The low-glycogen group produced consistently less power during the 8x5-minute intervals throughout the three weeks.
Time Trial Performance: Both groups improved their 60-minute time trial performance by a similar amount (~10%).
The Fat Oxidation Red Herring: The researchers noted that the low-glycogen group exhibited about 30% higher rates of fat oxidation. This finding is often highlighted by proponents of “train low.” However, as the performance data shows, this increased fat burning did not translate to superior endurance. The body simply adapted to use the fuel that was most available. It is a change in substrate utilization, not an enhancement of performance capacity.
When all the evidence is considered, the “train low” strategy is not the performance-enhancing shortcut it’s claimed to be.
The Core Mechanism is Flawed: The foundational premise that low glycogen potentiates p38 MAPK signaling was not observed in human studies. While low glycogen is a stressor, it does not appear to amplify this specific pathway more than normally fueled, high-quality training.
Performance is Compromised: Training in a glycogen-depleted state demonstrably reduces the quality of high-intensity work you can perform. Since the primary driver of adaptation is progressive overload—challenging the body with a demand it’s not used to—reducing power output is counterproductive.
Homeostasis and Training Status: A well-trained athlete’s body is remarkably good at maintaining cellular homeostasis. For a given workload, they experience less cellular stress than an untrained person. This is why some studies show less p38 activation in trained individuals. To elicit further adaptation, they must increase the training stress (ride longer or harder), not compromise it by removing fuel.
The Cost Outweighs the (Lack of) Benefit: Training with low glycogen has significant downsides:
Reduced training quality.
Increased perceived exertion.
Impaired recovery.
Negative mood and irritability.
Potential for compromised immune function.
Given that the evidence shows no superior performance benefit, these costs are not justified.
Do Not Train Fasted: This is the most extreme and counterproductive version of the “train low” protocol. It impairs performance and recovery with no proven upside.
Fuel for the Work Required: The most effective way to drive adaptation is to perform the highest quality training your body can handle. This requires adequate carbohydrate fueling before and during your sessions.
Focus on Performance, Not Substrate: Do not get caught up in trying to “train your body to burn more fat.” Your body will adapt its fuel usage based on your overall fitness. Focus on improving your power output and endurance through consistent, well-fueled, progressive training. The fat-burning adaptations will follow as a consequence of improved fitness, not as a direct goal.
In summary, while the molecular pathways like p38 MAPK are fascinating, the attempt to manipulate them through glycogen depletion is an ineffective strategy. The most reliable path to improvement remains the one proven by decades of coaching and application: fuel yourself properly and train hard.