Think Thrice

How the body generates energy for endurance exercise

Two people running on the road among trees

If you’ve ever exercised intensely, you’ve felt the feeling of not being able to continue. It might've been a trembling as you struggle to finish a push-up, or a burning in your chest that forces you to stop running.

Why can’t we endure in these situations?

Is it physical — do we run out of the energy needed to continue moving?

Is it mental — do we run out of willpower and give up?

If you pause and contemplate, I think you'll find, as I did, that your answers are either circular or vague. Accordingly, in this post I'd like to explore some of the concrete biological mechanisms underlying physical endurance in the human body.

Specifically, we'll look at:


Let’s start by establishing what endurance means. While it has multiple definitions, the one that captures some key ideas for our exploration is:

Endurance is the ability to resist a mounting desire to disengage effort.

This definition is concise but non-colloquial, so let’s break it down.

The first part of “resisting a mounting desire” captures the mental tug-of-war between continuing and stopping, where the latter strengthens over time. It matches the visceral experience I have when my endurance fails: I always want to stop before I do stop.1

The second part of “disengaging one’s effort” captures the idea that when we reach the end of our endurance, we don’t just keel over. Rather, we progressively disengage by slowing down or shifting our attention elsewhere.

These two ideas support an intuition that a mental component, which we can call willpower, is needed to maintain endurance.

We also have an intuition that there’s a physical component to endurance, independently of a mental aspect. We know that if we train, our bodies adapt and our endurance improves. If I just casually ran a race tomorrow, I’d run much faster than a fully-prepared “A” race a few years ago, where I exhausted every ounce of my willpower.

Let’s call this physical aspect energy. Putting these intuitions together yields the following model:

A basic model of endurance

...which isn’t very useful because the concepts of energy and willpower are too vague. So, let’s clarify them by exploring some of the biological mechanisms that underlie human movement.


We can describe the depletion of endurance as fatigue. An intuitive basis of fatigue is that it occurs because energy use exceeds supply. But what is energy, how is it supplied, and what’s using it?

For our purposes, energy can be defined as the potential for an object to do something (“work”). There are many ways to classify energy and the work that it does. For example, the human body harnesses the “chemical” energy stored in the bonds of biological molecules to perform the “mechanical” work of contracting a muscle. Energy typically needs to be stored and extracted at another point in space and time to apply it towards useful work.

The key form of energy storage in the human body is a molecule called adenosine triphosphate (ATP). Energy from the chemical bonds in food is extracted and stored in the chemical bonds of ATP. Put simply, ATP is the energy “currency” of the human body, and our cells only work when they're paid.

General structure of adenosine triphosphate (ATP), consisting of three phosphate groups and adenosine (ribose + adenine)

To extract the energy stored in ATP, the molecular bonds between its phosphate molecules are broken. The outermost phosphate bond in ATP is the most amenable to breaking off, and doing so creates adenosine diphosphate (ADP). This process requires the help of a protein catalyst or enzyme2 called adenosine triphosphatase (ATPase), which supports the chemical reaction alongside water.

ATPase breaks down ATP into a phosphate, ADP, and energy

However, most of the energy in the body isn’t stored in the form of ATP. Rather, it exists in shelf-stable “storage” forms like glycogen and triacylglycerols (fat)3. These can be broken down or metabolized into “usage” forms like glucose and glycerol + fatty acids, respectively, and then further into ATP.

General structure of glycogen (composed of glucose) and triacylglycerol (composed of glycerol and three fatty acids)

The storage form of energy relates to its total reservoir of potential ATP and how it’s metabolized, which determines the rate at which it generates ATP. In humans, fat stores around 50-fold more potential ATP than glycogen but is metabolized to ATP at half its rate.

Supplying energy (ATP)

Energy can be thought of as ATP in the context of the human body. ATP is primarily generated through metabolism of carbohydrate and fat4, which involves three general steps:

  1. Breaking down the storage forms of nutrients into usage forms
  2. Breaking down the usage forms into a molecule called acetyl-coenzyme A (acetyl-CoA), which generates a bit of ATP.
  3. Breaking down acetyl-CoA by extracting hydrogen and using it to generate a lot of ATP alongside oxygen.

Let’s examine the specific mechanisms that occur during these steps when metabolizing carbohydrate and fat.

Carbohydrate metabolism

Carbohydrates are a limited but powerful source of ATP in the human body. Glycogen is primarily stored in skeletal muscles and the liver5, and is metabolized to glucose when energy is needed. Cells can take up glucose into their internal environment and convert it to ATP through a process called glycolysis.

Glycolysis has two phases: rapid and slow. The rapid phase involves breaking down glucose into a molecule called pyruvate and in the process, rapidly extracts ~5% of the energy stored in a glucose molecule as ATP. This produces energy quickly, but isn’t sustainable due to the low extraction efficiency.

Glycolysis requires the help of an enzyme called nicotinamide adenine dinucleotide (NAD). During glycolysis, NAD is required to chemically convert particular input molecules to output molecules by binding to a hydrogen atom present in the input. In doing so, it allows another molecule to take the place of the hydrogen, such as phosphate. When NAD is bound to hydrogen (H), it becomes NADH.

Rapid glycolysis converts glucose to pyruvate and a bit of ATP, and requires help from the enzyme NAD which binds hydrogen (H+) to form NADH

The slow phase of glycolysis begins with breaking down pyruvate into acetyl-CoA and sending it through a process called the citric acid cycle (CAC). The CAC converts acetyl-CoA into various molecules with the help of NAD and generates NADH, carbon dioxide, and a bit of ATP in the process.

The processes described so far don’t explicitly require oxygen to function, and so are classified using the term *anaerobic* (not aerobic, where aerobic means oxygen-requiring) metabolism.

The citric acid cycle converts acetyl-CoA into various molecules with the help of NAD and generates NADH, carbon dioxide, and a bit of ATP

If there’s oxygen available inside the cell at this point, NADH unloads its hydrogen to a process called the electron transport chain (ETC) and reforms NAD. The ETC pumps hydrogen ions (H+) out of the local area, creating a concentration gradient where it wants to re-enter the area it was pumped out of. Like water flowing through a dam and turning turbines, hydrogen flowing down its gradient “turns” an enzyme called ATP synthase which attaches a phosphate to ADP, creating ATP.

The coupling of the ETC (which creates a hydrogen gradient) with ATP synthesis (using that gradient to create ATP) is called oxidative phosphorylation (OxPhos). This process extracts the remaining ~95% of energy stored in a glucose molecule as ATP. Accordingly, we want to keep sufficient levels of oxygen inside active cells to maximize OxPhos and create lots of energy sustainably.

Oxidative phosphorylation — the electron transport chain creates an inwards gradient of hydrogen ions that drives the creation of ATP by ATP synthase

The final step of the ETC consumes oxygen to proceed and without it, the hydrogen gradient disappears and ATP synthase stalls. Accordingly, the slow phase of glycolysis is typically classified as aerobic metabolism6. Intense exercise drives active cells to produce large amounts of NADH via glycolysis relative to rate of oxygen they receive. When a lack of oxygen stalls the ETC, NADH can’t reform to NAD by unloading its hydrogen to it. This indirectly stalls both the CAC and the rapid phase of glycolysis because they need NAD to function.

In an oxygen-deficient cell, NADH can’t unload its hydrogen into the ETC. To manage this, NADH instead unloads its hydrogen onto pyruvate to form a molecule called lactate, with the help of the enzyme lactate dehydrogenase7. Doing this reforms NAD without oxygen, which un-stalls the rapid phase of glycolysis and the CAC, allowing them to directly produce some ATP. When oxygen levels rise, unstall the ETC, and increase NAD levels, lactate can then be converted back to pyruvate. Lactate can also be shipped out of the active cell to the liver, which converts it to glucose that can be sent back to the active cell and used in glycolysis.

When lacking oxygen, pyruvate is converted to lactate in order to reform NAD. Lactate can be sent to the liver and converted to glucose which drives glycolysis

Altogether, lactate metabolism can be viewed as a mechanism that helps sustain ATP production during intense exercise that depletes cellular oxygen levels. However, since the rapid phase of glycolysis and the CAC only generate a bit of ATP relative to OxPhos, it doesn’t fully compensate for the reduced rate of ATP generation during oxygen deficiency.

Cellular waste: Acid

Some of the processes mentioned thus far generate “waste” in the form of molecules that are acidic. This includes:

Acid is considered a waste product when it builds up excessively because it impairs the function of the enzymes that catalyze metabolic reactions and extract energy from ATP. The body has several mechanisms to buffer changes in acidity, but these can be overwhelmed by high levels of glycolysis. Lactate represents one such mechanism: by binding to a free-floating hydrogen ion as it’s formed, it reduces the acidity of the area8.

Fat metabolism

Compared to carbohydrates, fats are a practically limitless but slow source of ATP. Triacylglycerol is a type of fat used for energy which is stored in muscles and fat cells and is broken down into glycerol and fatty acids.

Glycerol can be converted into an intermediate molecule in the rapid phase of glycolysis, generating ATP via OxPhos or lactate metabolism. Fatty acids can be converted to acetyl-CoA through a process called beta-oxidation which is then used in the CAC. Beta-oxidation involves cleaving 2-carbon acyl groups from the fatty acid and combining it with CoA, and requires support from NAD. Compared to rapid glycolysis and the CAC, beta-oxidation doesn’t directly generate ATP, so the “payoff” is all later (from metabolizing acetyl-CoA).

Fat metabolism — triacylglycerol is broken down to glycerol and fatty acids. Glycerol can be converted to an intermediate in rapid glycolysis and fatty acids can be converted to acetyl-CoA through beta-oxidation and enter the citric acid cycle

Altogether, fat and carbohydrate metabolism generate intermediate molecules of the same pathways — rapid glycolysis, the CAC, and the ETC — allowing them to reuse the same processes to generate ATP9.

However, one notable difference between them is that fat metabolism strictly depends on oxygen whereas carbohydrate metabolism can occur without it. This relates to regenerating NAD from NADH. Carbohydrate metabolism can regenerate NAD without oxygen through NADH unloading hydrogen onto pyruvate to form lactate. No similar mechanism exists for glycerol or fatty acids, so fat metabolism requires the ETC to regenerate NAD and is therefore strictly aerobic10.

Using energy and routes of fatigue

Intuitively, muscles are the main consumers of energy during exercise. “Muscles” include the skeletal muscles used in the activity as well as cardiovascular muscles (the heart and breathing muscles), which move blood to deliver nutrients to active cells and expel carbon dioxide. For the moment, we can consider these muscles as simple black boxes: energy (ATP) in, movement (work) out.

Having explored some types and mechanisms of metabolism, let’s return to the concept of fatigue. How might these mechanisms fail to provide sufficient energy to muscles? Some “metabolic” routes of fatigue might include:

Experiencing these conditions manifests as an inability to maintain a desired effort: struggling to complete a push-up or running slower. Which of these routes of fatigue occur during exercise depends on which metabolic systems it uses, which is mainly influenced by how intense the exercise is. Accordingly, exercise intensity determines which routes of fatigue occur. To clarify this idea, let’s examine the likely routes of fatigue11 for different intensities of running in the context of maximal efforts over a fixed duration12.

For short duration (~secs) maximal efforts like a 100m sprint, the small amount of “raw” ATP stored in the muscle provides most of the energy13. In this short timeframe, not even rapid glycolysis has much time to process glucose and generate ATP, let alone the CAC and OxPhos14. Accordingly, routes like depleting glycogen and waste overflow likely aren’t significant factors15. Rather, fatigue probably occurs due to depleting intramuscular ATP.

For moderate-duration (< ~2 mins) maximal efforts like a 400m run, high levels of rapid glycolysis can support the extended ATP needs, but also generates lots of acid. Glycogen stores aren’t depleted in this timeframe, so depleting top-level inputs isn’t an issue. At this duration, OxPhos begins to contribute but can’t handle all of the NADH produced by rapid glycolysis, which consequently forms lactate. Fatigue probably occurs due to waste overflow when the rate of lactate formation can no longer buffer the acid being produced.

For long-duration (~mins to hrs) maximal efforts like a 10,000m or marathon16, OxPhos provides the majority of the energy via the NADH generated from slow glycolysis. At this duration, fat metabolism begins to contribute, but most of the energy still comes from carbohydrate metabolism. This is probably because more ATP is generated per unit oxygen from using glucose compared to triglycerides. Maximal efforts can deplete glycogen stores in around 90 to 120 mins, so depleting glycogen becomes an issue here. In contrast, even a small amount of stored fat provides a large amount of energy, so fat depletion still isn’t a problem17. For maximal efforts at the shorter end of this spectrum (like a mile), cellular oxygen depletion becomes an issue as aerobic metabolism is pushed to the limit. For maximal efforts in the middle of this spectrum (~1 hr), a combination of cellular oxygen depletion and inadequate acidic waste clearance probably cause fatigue.

Relative contribution of metabolic systems during maximal efforts of varying duration

What about submaximal efforts over these durations? In general, as exercise intensity decreases, the body shifts from anaerobic to aerobic metabolism and uses fat over carbohydrate. This follows from reduced energy needs and oxygen consumption, both of which are conducive to fat metabolism, which is slower and requires more oxygen than carbohydrate metabolism per unit ATP.

Updating the model: Energy

Exercise intensity determines the balance of metabolic systems that fuel the effort, which in turn affects the likely routes of fatigue. This establishes the “physical” or “energy” contribution to endurance. Accordingly, let's update our model:

Initial model of endurance with the concept of “energy” expanded


We began this exploration with the intuition that a physical aspect like “energy” contributes to endurance separate of a mental aspect like “willpower”. To clarify the concept of energy, we defined it as the capacity to do so something and saw how it’s stored in the human body as various forms: ATP, glycogen, glucose, triglycerides, glycerol, and fatty acids. We examined how ATP is created from these forms of energy using metabolic processes like rapid glycolysis, the citric acid cycle, oxidative phosphorylation, and beta-oxidation.

Moving up, we explored how exercise intensity impacts the balance of metabolism that fuels it and how that relates to likely metabolic routes of fatigue. We saw that at maximal intensity, short duration efforts are limited by raw ATP storage, medium duration efforts are limited by acidic waste overflow, and long duration efforts are limited by glycogen storage or cellular oxygen depletion. We noted that if we need energy fast, we use anaerobic metabolism with carbohydrates and if we need a lot of energy, we use aerobic metabolism with fat.

In a follow-up to this post, we'll move on to explore and clarify the willpower component of endurance.

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  1. It’s remarkable how arresting the “stop” signals feel as they build up, despite having a deep determination to press on. Keep in mind that as we deplete our energy, our ability to think clearly degrades, making it difficult to override the “stop” signals consciously. Put simply, everyone has a plan until they get punched in the face.

  2. A catalyst increases the rate of a chemical reaction by reducing the energy it needs to occur, without being consumed itself. Catalysts composed of biological proteins are called enzymes, and virtually every process in the human body requires the help of particular enzymes to occur at a sufficient rate.

  3. Triacylglycerols are the main type of fat in the human body that is used for energy. There are other types of fats like cholesterol that are used to build cell membranes and hormones.

  4. Protein metabolism can also generate ATP by converting of the amino acid alanine to glucose in the liver. This might provide a small percentage of the total energy used during light exercise.

  5. Approximately 400 grams of glycogen is stored across all skeletal muscle and 100 grams in the liver, which increases as an adaptation to endurance exercise.

  6. It’s more specific to say that oxidative phosphorylation or the ETC are types of aerobic metabolism since the CAC doesn’t explicitly require oxygen. However, since these processes are a part of slow glycolysis, some texts will refer to slow glycolysis as aerobic glycolysis.

  7. This is the conventional model of how lactate is formed. More recent research suggests that lactate always forms, even under oxygen-rich cellular states, and is either converted to pyruvate or not based on oxygen levels.

  8. An incorrect belief is that glycolysis occurring without oxygen generates a molecule called lactic acid which dissociates into lactate and a hydrogen ion. This is used to imply that the generation of lactate impairs exercise performance by producing acid. In reality, no such mechanism occurs and lactic acid isn’t generated by any process in the body. Only lactate is generated and it strictly aids performance by acting as an acid buffer and a fuel source.

  9. Notice how explaining fat metabolism was much shorter than explaining carbohydrate metabolism? Thank evolution for developing some DRY biology that reduces word counts in blog articles and textbooks alike!

  10. There’s some nuance here I couldn’t find a clear explanation for. Typically, both carbohydrate and fat metabolism occur simultaneously so it’s conceivable that the NAD regenerated from forming lactate can be used to drive beta-oxidation instead of glycolysis. This would imply that fat metabolism technically also doesn’t require oxygen. However, it seems that because beta-oxidation only generates acetyl-CoA for the CAC without creating ATP in the process, expending NAD on beta-oxidation just blocks the pipeline at a later stage (the CAC, which requires NAD) without getting any ATP for it. In contrast, expending that NAD to drive rapid glycolysis or the CAC gets you some ATP.

  11. I say likely because there isn’t a complete & definitive description of fatigue for any physical activity. There are only mechanisms, like different types of metabolism, and reasoning based on understanding those mechanisms what might limit them. A high-level phenomena like movement is produced from integrating basically every system of the human body, so science (“exercise physiology”) has yet to “solve” the causes of fatigue. Still, much has been learned and successfully translated to training protocols and fueling strategies to improve physical performance. The INEOS 1:59 Challenge is a great example of this.

  12. By “maximal effort”, I mean the effort level that could be sustained over the entire duration that would produce the best performance. For example, you could start off a marathon sprinting, but you wouldn’t be able to sustain that effort level. So “maximum” means a more moderate effort relative to a sprint, or a lower “absolute” effort level.

  13. Another energy-storage molecule called phosphocreatine can immediately provide its phosphate to ADP to create ATP, and also contributes to such an effort.

  14. One way to think about this is that within the timespan of the effort, rapid glycolysis might generate just 1 out of the 10 units of ATP expended while the CAC and oxidative phosphorylation don’t generate any.

  15. Technically, waste overflow might be a cause of fatigue if the “spike” in ATP breakdown and consequent acid production overwhelms the buffering system. However, there seems to be mixed evidence for and against this being the case in short-duration maximal efforts.

  16. From the perspective of human metabolism, what’s considered a short, moderate, and long duration is very different than our everyday perception. Still, if you've ever found yourself at the last minute of an all-out mile, you can probably also agree that 60 seconds is a long time.

  17. Assuming that running a marathon requires 2500 calories and you could get all your energy from fat metabolism, you’d only need 278g of fat for the effort. A 60kg person at 10% body fat would have around 6000g of fat — assuming it was all triglycerides, this would be enough to fuel around 22 marathons. Depleting fat stores is basically never a problem - the issue is that the rate of energy generation from fat metabolism is too slow for most performance-oriented physical activities.