Fatigue signals are often related to deviations in pH range from optimal for enzymatic function, not necessarily depletion of energy stores or oxygen.

“Effectively, muscle contraction happens because enzymatic function occurs within a fairly specific pH range, right? So if it gets extremely acidic, it doesn't like it. And so whether you're running through aerobic glycolysis or anaerobic, or anything else, all these things require, even ATP hydrolysis requires ATPases. Enzymes don't function well outside of this fairly special range. So what happens is generally fatigue, the sensations of fatigue are actually caused by some signal that hey, we're starting to run out of pH. Or we're getting in the wrong range. You're not out of gas usually, you're not too low on oxygen. You're not running low on muscle glycogen yet. You're typically going to see signs, or feel signals of fatigue way prior to that, mostly being pH issues.”