Fatigue is based on actual v. Sim usage. Usage is the key here. Take for example the 1994 Greg Maddux. He pitched 202 innings, but in only 117 games. That usage rate is equivalent to a pitcher who threw 280IP over a 162 game season.
If you take it 1 step further and use the historical MLB average of 16 pitches/inning, you get 16 * 280 IP = 4480 pitches. That's what you could expect to get out of Maddux in the regular season. Using him more than that, will cause performance to decrease and you'll see a rise in his ERA.