If you overwork a RB one season, it will affect his performance in future seasons.
Your defensive line will also play better if it's fresher, so it's a good idea to give your backups some snaps.
Last season I also found value in changing my gameplan up from time to time.
In the first game against Anchorage I went blitz heavy and Alex D. Smith made me pay for it dearly.
In the second game I was a lot more conservative on defense and shut that overrated turd down.
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