1. As far as I've heard and can tell fatigue only effects the D-line and HB's. If your HB has too many carries in a season then they may perform worse.

2. You currently cannot change your depth chart for different packages so if you're running a 4-3 I would assume it would be best to stick to DE4 ends, although, I'm not sure how much of a penalty, if any, you'd receive for swapping to the DE3's.