The VMO is stressed more by toe-out. By "uncomfortable" do you mean it hurts? Hurts more than your other leg muscles? Is the only muscle that hurts? Only the muscle hurts, not the connective tissue? Or doesn't hurt, just feels weird? One of my mottos is if a ride didn't hurt, I wouldn't be doing it. So often, hurting muscles is a good thing. OTOH, maybe it's not the VMO that hurting, but the inside of your kneecap. That's a whole 'nouther matter. That shouldn't hurt.

I don't think moving the saddle back and forth changes knee action. Up and down, yes. So when you go to change setback, measure saddle height first and reset that height afterwards.