Genetic model for the chronic activation of skeletal muscle AMP-activated protein kinase leads to glycogen accumulation

The AMP- activated protein kinase ( AMPK) is an important metabolic sensor/ effector that coordinates many of the changes in mammalian tissues during variations in energy availability. We have sought to create an in vivo genetic model of chronic AMPK activation, selecting murine skeletal muscle as a representative tissue where AMPK plays important roles. Muscleselective expression of a mutant noncatalytic gamma 1 subunit ( R70Q gamma) of AMPK activates AMPK and increases muscle glycogen content. The increase in glycogen content requires the presence of the endogenous AMPK catalytic alpha- subunit, since the offspring of cross- breeding of these mice with mice expressing a dominant negative AMPK alpha subunit have normal glycogen content. In R70Q gamma 1-expressing mice, there is a small, but significant, increase in muscle glycogen synthase ( GSY) activity associated with an increase in the muscle expression of the liver isoform GSY2. The increase in glycogen content is accompanied, as might be expected, by an increase in exercise capacity. Transgene expression of this mutant AMPK gamma 1 subunit may provide a useful model for the chronic activation of AMPK in other tissues to clarify its multiple roles in the regulation of metabolism and other physiological processes.