Lens can manage it. They have a stadium with a capacity three times the town's population and yet they manage to operate in France at a top level.
PSV can manage it, they are a top team in Europe and can survive despite Eindhoven's relatively small population base (when compared with the likes of Ajax or Feyenoord) because of the interest of the Philips electronics company. (Meadowbank Thistle - which later became Livingstone, began with similar support from Ferranti)
I'd like to think the chap from St Johnstone was right because Hull City DOES have the population base to keep it in the Premiership and I'd love to see them stay up (my grandfather played Rugby for Hull back in the 1890s and 1900s so I have a soft spot for the City).
As for Gretna, yes, sadly a lot of people have invested in something which proved unsustainable, a small town on the Anglo-Scottish border qualifying for Europe and getting into the Scottish top flight. Did they fail though because of a lack of a population base? Given the success of Lens, and to a lesser extent Ebbsfleet United, I'd say no. What is needed is not necessarily a big population base but some kind of innovative financial package that enables the club to compete on a sporting level quite separately from the need to perform financially.