I've wondered about this for the longest time, but only recently started asking myself about it when I took up bass and effectively had to teach myself to play all over again from scratch.
Long story short: I'm a leftie who's played right-handed guitar for years but never felt comfortable playing standing up. I found it easier to play when sitting down. I figured I was learning the 'wrong' way around so should expect difficulty and discomfort, but after buying a leftie bass this year I'm experiencing the same thing. I feel that the entire instrument, especially the fretboard, is at a really awkward angle for fretting notes unless I sit down to play it.
Is it normal to find playing difficult while standing? Or is there a fault in my technique/posture that makes it so hellishly uncomfortable in comparison with playing while seated? Could the problem be that you're supposed to learn by feel rather than looking at what your hands are doing, so seated playing has allowed me to acquire a sight-based 'lazy' style?
Since almost all live musicians I've ever seen play standing up I'm not sure if I'm Doing It Wrong!
Guitar rig: CIJ Fender Jazzmaster -> TU-3 -> Triangle Muff clone -> M.A.S.F. Lavender Head -> Nux Modcore -> PS-2 -> DD-500 -> EHX Cathedral -> RV-5 -> Matamp Mini
Bass rig: Fender MIM Jazz Bass -> TU-2 -> Proco RAT -> Sansamp BDDI
"...So now you know the true secret to great tone: all the espresso you can handle."