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Am J Physiol Endocrinol Metab (November 14, 2006). doi:10.1152/ajpendo.00369.2006
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Submitted on July 24, 2006
Accepted on November 13, 2006

A Genetic Model for the Chronic Activation of Skeletal Muscle AMP-activated Protein Kinase Leads to Glycogen Accumulation

Laura Barre1, Christine Richardson2, Michael F Hirshman3, Joseph T. Brozinick4, Steven Fiering5, Bruce E. Kemp6, Laurie J. Goodyear3, and Lee A. Witters7*

1 Medicine, Dartmouth Medical School, Hanover, New Hampshire, United States
2 Medicine, Dartmouth Medical School, Hanover, New Hampshire, United States; Hanover, New Hampshire, United States
3 Joslin Diabetes Center, Metabolism Section, Harvard Medical School, Boston, Massachusetts, United States
4 Eli Lilly and Company, Indianapolis, Indiana, United States
5 Immunology, Dartmouth Medical School, Hanover, New Hampshire, United States
6 St. Vincent's Institute of Medical Research, CSIRO Health Sciences and Nutrition, Australia
7 Department of Medicine, Endocrine-Metabolism Division, Dartmouth Medical School, Hanover, New Hampshire, United States

* To whom correspondence should be addressed. E-mail: lee.a.witters{at}dartmouth.edu.

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 non-catalytic {gamma}1 (R70Q{gamma}1) subunit 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 physiologic processes.




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