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

¹Departments of Medicine, Biochemistry, and Microbiology and Immunology, Dartmouth Medical School, and Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire; ²Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts; ³Eli Lilly and Co., Indianapolis, Indiana; ⁴St. Vincent's Institute and CSIRO Molecular and Health Technologies, Fitzroy, Victoria, Australia

Submitted 24 July 2006 ; accepted in final form 13 November 2006

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. Muscle-selective expression of a mutant noncatalytic 1 subunit (R70Q) of AMPK activates AMPK and increases muscle glycogen content. The increase in glycogen content requires the presence of the endogenous AMPK catalytic -subunit, since the offspring of cross-breeding of these mice with mice expressing a dominant negative AMPK subunit have normal glycogen content. In R70Q1-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 AMPK1 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.

glycogen synthase; exercise; transgenic mice

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