Original episode & show notes | Raw transcript
For decades, the conversation around endurance nutrition and training has been dominated by a seemingly simple dichotomy: burning fats versus burning carbohydrates. Athletes and coaches have pursued strategies—from fasted training to ketogenic diets—in an attempt to “teach” the body to better utilize its vast fat reserves, hoping to spare finite glycogen stores for critical moments. While these strategies are rooted in a logical premise, they often miss the more profound, underlying mechanism of endurance adaptation.
This document, inspired by the detailed discussion in the Empirical Cycling Podcast, aims to move beyond this surface-level debate. We will explore the intricate world of cellular bioenergetics to reveal that the true hallmark of elite endurance is not simply the type of fuel used, but the sheer capacity and efficiency of the cellular machinery that processes it. The ultimate goal of endurance training is not to force a choice between fuels, but to build a more robust and resilient metabolic engine. The key to that engine is the mitochondrion.
To ground our discussion, we begin with the findings of a pivotal study examined in the podcast.
The Study: Carbohydrate Improves Exercise Capacity But Does Not Affect Subcellular Lipid Droplet Morphology, AMPK, and P53 Signaling in Human Skeletal Muscle.
The Setup: Trained cyclists performed a 180-minute ride at a moderate intensity (roughly their “LT1,” or the point where lactate begins to rise above baseline). They were divided into three groups, receiving either 0, 45, or 90 grams of carbohydrates per hour. Before and after the ride, muscle biopsies were taken to analyze changes at the cellular level.
The Performance Result (As Expected): Performance in a subsequent high-intensity time trial was directly proportional to carbohydrate intake. The 90g/hr group lasted longest (around 4 minutes), while the 0g/hr group could only sustain the effort for about 2 minutes. This confirms a well-established fact: carbohydrates are essential for high-intensity performance.
The Substrate Result (Also As Expected): The 0g/hr group burned significantly more fat, both from the bloodstream and from intramuscular stores (triglycerides). The 90g/hr group, conversely, derived most of its energy from carbohydrates.
The Paradoxical Finding: Here is the crucial insight. Despite the vast differences in fuel usage, the glycogen depletion from muscle fibers was nearly identical across all groups. Furthermore, and most importantly, the key signaling proteins responsible for triggering aerobic adaptations (like mitochondrial biogenesis, the creation of new mitochondria) showed no significant difference between the groups. In fact, some markers showed a slight, albeit not statistically significant, improvement in the high-carb group.
This study presents a fundamental challenge to the “train low, race high” paradigm. If restricting carbohydrates forces the body to burn more fat but doesn’t enhance the signal for adaptation, what is the true driver of endurance? The answer lies not in what you burn, but in the machinery that does the burning.
To understand endurance, we must first understand energy. The universal energy currency of the cell is Adenosine Triphosphate (ATP). However, the energy in ATP doesn’t come from “breaking” its phosphate bonds, as is commonly taught. It comes from the cell’s ability to maintain a state of profound disequilibrium.
Mass Action Ratio: If left to its own devices, the reaction of ATP breaking down into ADP (Adenosine Diphosphate) and a phosphate group would reach an equilibrium where there would be roughly 10 million ADP molecules for every one ATP molecule. In a living cell, this ratio is inverted: there are approximately 1,000 ATP molecules for every one ADP.
The Potential for Work: The cell is holding this ratio 10 orders of magnitude away from equilibrium. This massive chemical imbalance is like a stretched rubber band or a compressed spring. It is this immense potential energy, this “desire” to rush towards equilibrium, that gives ATP the power to fuel every muscle contraction, nerve impulse, and cellular process. If the ratio were at equilibrium, ATP would have zero capacity to do work, and the cell would be dead.
How does the cell maintain this incredible disequilibrium? This is the primary job of the mitochondria.
The Mitochondrial Membrane Potential: Mitochondria create an electrochemical gradient—a difference in charge and concentration—by pumping protons (hydrogen ions) across their inner membrane. This creates a powerful “proton-motive force,” analogous to the water stored behind a dam or the charge stored in a battery.
The ATP Synthase “Turbine”: This stored potential energy is then harnessed by a remarkable molecular machine called ATP synthase. As protons flow back across the membrane through this complex, they cause it to spin like a turbine, physically forcing ADP and phosphate together to create ATP.
Crucially, this process is self-regulating. When ATP is used for work, it becomes ADP. The presence of ADP instantly signals the ATP synthase “turbine” to spin, drawing on the membrane potential to regenerate ATP. The system doesn’t wait for a command; the demand for energy automatically drives its own supply. The job of the food we eat (fats and carbs) is simply to supply the electrons to the electron transport chain, which is the machinery that pumps the protons and “recharges” the mitochondrial battery.
A common misconception is that the body meticulously tracks every molecule of fat and carbohydrate. In reality, once these fuels enter the metabolic furnace, their original identity is lost.
Information Loss: Whether it comes from a fatty acid, a glucose molecule, or even a lactate molecule, the fuel is ultimately broken down into common intermediates like Acetyl-CoA, and its energy is captured in “reducing equivalents” like NADH and FADH2. These are the universal inputs for the electron transport chain. The mitochondria don’t know or care where the NADH came from; they only care about its availability to recharge the membrane potential. This is a fundamental principle: metabolic pools are state-dependent, not path-dependent.
Metabolic Control: Two Key States: We can simplify the complex regulation by thinking about two distinct but connected states:
The Cell’s Energy State (Cytosol): This is determined by the ATP/ADP ratio in the main body of the cell. When this state is stressed (i.e., ATP levels fall and ADP/AMP levels rise), it triggers rapid, but unsustainable, energy systems like anaerobic glycolysis.
The Redox Balance (Mitochondria): This is the ratio of reduced (NADH) to oxidized (NAD+) equivalents inside the mitochondria. When the mitochondrial “battery” is being used, it creates a “redox demand,” signaling a need for more NADH to recharge it. This drives sustainable, aerobic metabolism.
A well-trained athlete’s cell can meet a high redox demand without significantly stressing its overall energy state. An untrained person’s cell cannot. This is the key difference that determines endurance.
If the adaptive signal is the same regardless of fuel, why does endurance training work? Because the primary adaptation is not a change in fuel preference, but an increase in the quantity and density of mitochondria. A greater mitochondrial mass provides three profound advantages:
Enhanced Substrate Processing (More Surface Area): More mitochondria mean more surface area packed with the transporters and enzymes needed to pull fats and lactate from the bloodstream and process them. This increases the maximum rate at which the aerobic system can operate.
Improved Energy Distribution (Shorter Distances): ATP diffuses poorly through the cell. Having a dense network of mitochondria distributed throughout the muscle fiber, close to where energy is needed, is like having a power outlet in every corner of a room. It makes energy delivery faster and more efficient.
Distributed Workload & Homeostasis (The Crucial Point): This is the most important and least appreciated benefit. Imagine one person is tasked with bailing out a rapidly filling boat. They will quickly become overwhelmed. Now imagine 1,000 people bailing. Each person works far less, and the boat stays afloat.
This is what happens in the muscle cell. With a vast mitochondrial network, the immense energy demand of exercise is shared. Each individual mitochondrion only needs to discharge a tiny fraction of its membrane potential to contribute to the total ATP production.
Because no single mitochondrion is overly stressed, the overall cellular energy state remains stable. The ATP/ADP ratio is protected.
Since the energy state is stable, there is no trigger for emergency, anaerobic glycolysis. This is how mitochondrial density spares glycogen. It’s not by “preferring” fat; it’s by being so good at producing energy aerobically that the anaerobic system is never called upon until intensities become truly maximal.
This model explains the observable differences between athletes. The local hero with a 400-watt FTP but poor endurance and the World Tour professional with the same FTP but incredible durability are separated by their mitochondrial volume.
The pro can ride for hours at a high percentage of their FTP, primarily oxidizing fat, because their massive mitochondrial network can easily meet the redox demand without stressing the cell’s energy state. Their glycogen is preserved for the race-winning attack.
The amateur, with fewer mitochondria, must rely on glycolysis much earlier. Their cellular energy state becomes stressed at a lower power output, leading to lactate accumulation, a higher rate of perceived exertion, and rapid glycogen depletion.
This understanding also reveals the flaws in models like VLA-Max, which posits that glycolytic activation increases linearly with exercise intensity. This is only true in a system with a fixed mitochondrial capacity. It fails to account for the fact that training—specifically, building more mitochondria—fundamentally changes this relationship. An elite athlete can operate at a much higher absolute power output with less glycolytic contribution than an amateur.
The ultimate lesson from this deep dive is one of elegant simplicity. The goal of endurance training is to create a cellular environment that is profoundly resilient to the stress of exercise. The most effective way to do this is to stimulate the biogenesis of new mitochondria.
The evidence suggests that the primary stimulus for this is the work itself—the duration and intensity of the exercise—not the manipulation of substrate availability. While burning more fat is a consequence of having a large mitochondrial mass, restricting fuel during training does not appear to be a shortcut to building it. In fact, by limiting performance, it may even be counterproductive.
Therefore, the most practical and scientifically sound advice is to focus on the fundamentals:
Progressive Volume: Consistently challenge your body with sufficient duration of training.
Targeted Intensity: Incorporate threshold and VO2 max work to stimulate the full spectrum of adaptations.
Fuel for the Work Required: Provide your body with the fuel it needs to perform the training, recover, and adapt.
The secret to elite endurance isn’t a secret at all. It’s the cumulative result of consistent, intelligent, and well-fueled work that builds, cell by cell, a superior metabolic engine.