Using two hands for key combinations is step one to avoiding RSI.
If you need to keep your hands on the mouse (for example, CAD or video editing) then get a keyboard with programmable macro keys, or a separate macro pad.
For example, a Kinesis Freestyle Pro, or a Koolertron.
With cmd based keyboard shortcuts, your hand basically forms the default resting limp hand position, with your thumb on the cmd button, and your index finger lazily and easily finding the other key to complete the shortcut. Your thumb is basically always there anyway due to the spacebar. It's a much more natural movement.