Original episode & show notes | Raw transcript
In the world of endurance physiology, few molecules are as famous as AMP-activated protein kinase (AMPK). It’s often called the “master metabolic regulator” or a “cellular energy sensor.” Its job is to monitor the energy status of a cell and, when energy levels get low, to flip a series of switches that ramp up energy production and shut down non-essential energy consumption. This makes it a primary driver of the endurance adaptations we seek from training, such as the creation of new mitochondria (mitochondrial biogenesis).
The podcast explores a fascinating and nuanced aspect of this story, centered on a 2009 paper that revealed AMPK doesn’t just sense low energy—it also acts as a glycogen sensor. It can directly detect how much fuel is left in the cell’s “gas tank.” This discovery led to a wave of interest in “train low” strategies, based on the hypothesis that exercising with depleted glycogen could amplify the signals for adaptation.
This document will walk through the science in detail, exploring:
The fundamental role of AMPK in exercise.
The key experiments that proved AMPK can sense glycogen.
The critical lesson on why this molecular finding doesn’t directly translate into a superior training strategy.
To understand the core of the discussion, we first need a solid grasp of what AMPK is and what it does.
The Cellular Energy Currency: Every cell runs on adenosine triphosphate (ATP). When ATP is used for work (like muscle contraction), it loses a phosphate group and becomes adenosine diphosphate (ADP). The cell’s primary goal is to maintain a very high ratio of ATP to ADP, keeping it far from equilibrium. A drop in this ratio signals an “energy crisis.”
AMPK as the Sensor: As exercise intensity increases and ATP is used rapidly, the cell works to regenerate it. One mechanism involves converting two ADP molecules into one ATP and one adenosine monophosphate (AMP). A rise in AMP levels is the clearest signal that the cell is struggling to keep up with energy demand. AMPK is the protein that senses this increase in AMP.
The Dimmer Switch Effect: AMPK activation isn’t an on/off switch; it’s a dimmer. The more AMP that is present (i.e., the harder the exercise), the more active AMPK becomes.
Key Actions of Activated AMPK: When AMPK is activated, it orchestrates a global shift in the cell’s metabolism from energy storage (anabolism) to energy production (catabolism). Its key effects include:
Increases Glucose Uptake: Signals for GLUT4 transporters to move to the cell surface, pulling more glucose from the blood.
Increases Fat Breakdown: Ramps up fatty acid oxidation to generate more ATP.
Increases Glycolysis: Boosts the breakdown of glycogen for immediate energy.
Inhibits Synthesis: Shuts down energy-expensive processes like the creation of glycogen, fatty acids, and protein.
Stimulates Mitochondrial Biogenesis: This is the big one for endurance athletes. AMPK activation is a primary signal that tells the cell, “We need more power plants!” leading to the creation of new mitochondria.
The podcast centers on a paper titled, “The glycogen binding domain on the AMPK β subunit allows the kinase to act as a glycogen sensor.” This research was prompted by observations in humans that AMPK activity was significantly higher when exercising in a glycogen-depleted state compared to a glycogen-loaded state. This was an association, but the paper sought to find the direct, mechanistic link.
AMPK is a complex protein made of three distinct parts, or subunits, that work together:
Alpha (α) Subunit: The “catalytic” or action subunit. This is the part that actually adds phosphate groups to other proteins to change their function (an action called phosphorylation).
Gamma (γ) Subunit: The “regulatory” subunit that binds to AMP and ATP. This is the primary energy-sensing component.
Beta (β) Subunit: This subunit acts as a scaffold, holding the alpha and gamma subunits together. Crucially, researchers discovered it contains a specific section of amino acids called a glycogen-binding domain (GBD).
The hypothesis was that this GBD allows the entire AMPK complex to physically attach to glycogen particles within the cell.
The researchers performed a series of elegant experiments to prove their hypothesis. The podcast walks through this logical progression.
Question: Does the glycogen-binding domain (GBD) on the beta subunit actually bind to glycogen?
Method:
They isolated the genetic code for just the GBD from rats.
They inserted this code into bacteria, causing the bacteria to produce the GBD as part of a larger, easily identifiable protein.
They mixed this new protein with glycogen particles.
Using column chromatography and centrifugation, they separated the heavy glycogen particles from the rest of the solution.
They then analyzed what was stuck to the glycogen using gel electrophoresis (the “Jello tray” analogy, which separates proteins by size).
Result: The protein containing the GBD was found stuck to the glycogen pellet, while a control protein without the GBD was not. This demonstrated a direct physical bond.
Question: If we break the GBD, does it stop binding?
Method:
The GBD has a sequence of amino acids that is “highly conserved,” meaning it’s nearly identical across many species (rats, flies, yeast), which implies it has a critical function.
The researchers created a new version of the protein where they mutated these key, conserved amino acids, replacing them with simple, non-functional ones.
They repeated the binding experiment from step 1.
Result: The mutated protein completely lost its ability to bind to glycogen. This confirmed that this specific, conserved sequence was responsible for the binding function.
Question: How does this binding affect AMPK’s activity?
Method:
They placed active AMPK in a solution and measured its activity as they added increasing amounts of glycogen.
In a crucial follow-up, they repeated this experiment but also added AMP, the primary activator of AMPK.
Result:
As glycogen concentration increased, AMPK’s activity was progressively inhibited. This reframed the entire concept: it’s not that low glycogen activates AMPK, but rather that the presence of glycogen suppresses it. The theory is that when AMPK is physically bound to a large glycogen particle, it is “sequestered” or held in place, unable to act on its other targets in the cell.
Even in the presence of the powerful activator AMP, adding glycogen still significantly inhibited AMPK activity. This proved that glycogen sensing is a separate and powerful regulatory mechanism, independent of the cell’s immediate AMP/ATP energy status.
Conclusion from the Lab: The evidence is definitive. AMPK can act as a glycogen sensor. When glycogen stores are high, AMPK binds to them and is inhibited. As glycogen is used up during exercise, AMPK is released and becomes free to signal for adaptations.
This is the most important lesson from the podcast. Based on the molecular evidence, one could draw a seemingly logical conclusion:
“Since low glycogen leads to higher AMPK activation, training in a low-glycogen state should produce a stronger signal for adaptation and lead to superior endurance gains.”
This is the rationale behind “train-low” strategies like fasted rides or delayed feeding post-exercise. However, this conclusion makes a leap that is not supported by broader scientific evidence.
Why the Direct Translation Fails:
In-Vitro vs. In-Vivo: The experiments were done in-vitro (in a dish). A living organism (in-vivo) is infinitely more complex, with countless overlapping systems.
Magnitude and Duration: A measurable increase in AMPK activity in a lab dish doesn’t automatically mean it’s a large enough increase, for a long enough duration, to cause a meaningful difference in real-world adaptation compared to normal training.
Performance is the Goal: The ultimate measure of a training strategy’s success is performance. The overwhelming body of literature on low-glycogen training shows that while it can increase fat oxidation, it does not improve performance and often impairs it by reducing the capacity for high-quality, high-intensity training.
Negative Consequences: Strategies like delayed feeding have been shown to impair recovery, disrupt metabolic health, and decrease performance the following day, even if glycogen is eventually replenished.
The podcast uses the analogy of ice cream sales and shark attacks. They are correlated (both rise in the summer), but one does not cause the other. Similarly, while higher AMPK activity is associated with low glycogen, forcing a low-glycogen state is not the cause of superior long-term adaptation.
The journey of this paper is a perfect illustration of the scientific process. It started with an observation in athletes, led to a brilliant series of experiments to uncover a molecular mechanism, and generated a new hypothesis.
However, the final step is always to bring that hypothesis back to the real world and test it. In this case, when the “train-low” hypothesis was tested, it did not hold up in terms of performance outcomes.
The key lessons are:
Mechanism is Not Outcome: Discovering a molecular pathway is not the same as validating a training intervention.
Performance is the Guiding Light: For athletes and coaches, physiological changes must ultimately translate to improved performance to be considered beneficial.
Be Skeptical of “Biohacks”: Biological systems are robust and complex. It’s rarely possible to “hack” a single pathway for a net positive gain without unintended consequences. The best stimulus for adaptation remains consistent, well-fueled, and progressive training.
This research remains incredibly valuable for scientists to understand the intricate regulation of cellular metabolism. But for athletes, the message is clear: the evidence strongly supports fueling your work appropriately to maximize training quality, recovery, and, ultimately, performance.