Muscles store some energy in the form of glycogen for quick and easy access. Glycogen is important for the energy needed for strength exercises such as lifting. Repeated use of a muscle depletes these glycogen stores, so even when the rest of your body feels rested, the muscle takes a bit longer to recover (like hours, compared to minutes for your heart rate to go down).
Until someone more knowledgable can answer: It’s probably because ATP (short-term energy source) gets depleted and lactic acid builds up (when it’s anaerobic exercise).
IIRC for some reason there is also a neurological component where your nervous system get “exhausted” for reasons which are not fully understood.
In order for your muscles to move, they require energy. Energy at a cellular level is provided by “burning” glucose to make energy carrier ATP (the technical term is aerobic glycolysis). Like normal burning this proces requires a lot of oxygen that is provided through red blood cells. If the exercise is demanding enough you require more ATP than your cells can produce with the supply of oxygen being a limiting factor. At that point your cells will produce extra ATP through a proces that doesn’t require oxygen. Known as anaerobic glycolysis or the lactic acid cycle. This has lactic acid as a byproduct, which builds up in your muscles creating a less ideal environment therefore you lose strength.
So buildup of lactic acid due to insufficient oxygen supply causes your muscles to fatigue.
The reset happens when all the lactic acid is removed from your muscles and the ATP is again supplied through aerobic glycolysis.
If your muscles and stamina improve over time your muscles will improve blood supply and therefore more oxygen, giving you more clean burning to supply ATP. That is a reason some athletes take performance enhancing drugs like EPO which stimulate red blood cell production, delaying the build up of lactic acid in the muscles.
Fun fact; some organisms, like yeast, have a different anaerobic glycolysis system. When yeast is deprived of oxygen it will also produce ATP through anaerobic glycolysis, but instead of lactic acid the byproduct is ethanol i.e. alcohol. Therefore you have to make sure that when brewing beer or wine there is no oxygen coming into the fermentation vessel, otherwise the yeast will switch to the more efficient aerobic glycolysis and not produce any alcohol.
Your muscles are running low on rapidly available energy and need to replenish it, [Here is a graph that shows energy sources during strenuous activity](https://www.researchgate.net/publication/333902223/figure/fig3/AS:1086068711530568@1635950367918/The-energy-systems-that-contribute-to-sport-practice-The-phosphagen-system-ATP-CP-is.jpg).
You start out with ATP (energy carrier of the cell) floating around but this is depleted within a second or two. Phosphocreatine then can regenerate some of the ATP while glycolysis ramps up. So far no oxygen was needed but now the muscle has depleted its phosphocreatine reserve and has begun to generate lactic acid as a byproduct of regenerating a reactant of glycolysis called NAD. This process slows as lactic acid builds up and glycolysis will slow due to a lack of NAD.
Now you have reached the point where you cant lift any more, your muscles have run out of available energy. If you wait a little bit the lactic acid will be carried away by your blood and metabolized in the liver. Meanwhile the muscle regenerates phosphocreatine and ATP levels return to normal and you are ready to lift more weight.
ALY5: let’s say you have a car with a full gas tank, but also has a long flexible tube connected to the gas station. You drive a few miles then run out of gas so you have to stop. Now you have to wait a bit for more gas to be pumped to the car from the gas station. Once the tank is full again you can keep going. Eventually the gas station will be empty and your engine will be overheating and worn out so you have to stop for longer to wait for fuel reserves to be replenished and to make repairs to the engine. Your bicep is the car/engine and the fuel is glycose/ATP/glycogen etc.
The simplest answer is that your muscles run out of energy.
Human cells store energy in ATP, which is a complext protein that has three phosphates squeezed together like a spring. When you excercise you run through ATP faster than your body can replace it and when it’s all gone the muscles simply can’t move. Thankfully, ATP can be easily replaced so long as your body has sugar and oxygen to burn.
There is some interesting science that points to a combination of mental and physical endurance. The idea is called Central Governor Model and it is the hypothesis is that there is a mechanism that prevents the body from “exercising” itself to death. From my understanding it is a feedback loop between the muscles and brain. Researchers aren’t sure if the fatigue signal comes from the brain or the muscles.
You can listen to a podcast about this topic as it relates to the world record for pull ups in 24 hours. [https://www.outsideonline.com/podcast/pull-artists/](https://www.outsideonline.com/podcast/pull-artists/)
You can read about it as it relates to runners here: https://thereader.mitpress.mit.edu/running-and-the-science-of-mental-toughness/
Aside from the energy storage issue other people have alluded to, there’s also a mechanical component: when you contract your muscles, they can block your blood flow (for example when clenching your hand into a fist). The same can happen in your arms and legs when doing consistent or repeated contractions (like holding a weight, flexing muscles, etc). Aside from your energy stores running out, the new energy has a much harder time getting to your muscle cells, and the “garbage” coming out of your muscles cells finds it harder to leave.
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