I think it's related to the auto-sub setting also. I played a game with my tempo set to Aggressive (which has the description of causing players to fatigue quicker) and running a lot of hurry-up because I was trying to emulate OU's quick-paced offense. By the 4th quarter I was playing with my entire 2nd string of receivers because the first string was evidently too tired. I've also seen this happen with my RB at times, especially if they break a really long run. Once, my KR/
PR/#2RB returned both a kickoff and a punt for a touchdown in the 1st half of a game and he didn't play the entire rest of the game.
I haven't messed with my auto-sub settings yet to see if this is fixable or not.