Hoo boy, this one is tough...
Had Charles II de Valois-Angouleme, the Duc d'Orleans not contracted the plague, then this would definitely weaken France, since these territories would've made him equal to his father Francis I (and his brother Henry II, who would succeed him in 1547) in terms of political power. It was assumed that this was the intent of Charles V, to divide and weaken France, and thus forever prevent further conflicts over there sovereign right to the Italian states.
Either way, I'd probably see it as a France-screw, even if they regain Franche-Comte or gain the Low Countries, though it largely depends on if the French Protestants would play a role in this. I'd find it interesting if he ended up marrying Maria, over Anna. While he would have the riches of the Low Countries, I wonder how the Dutch Protestants would react under French rather than Ultracatholic Spanish rule.
On the flip side, if Charles sires a few generations of heirs, they might have a shot at getting the French throne anyway, but butterflies are a fickle thing.