Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 38, Pages 16092-16097Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1105062108
Keywords
TBC1D1; PGC1-alpha; AS160; type 2 diabetes; obesity
Categories
Funding
- National Health and Medical Research Council
- Australian Research Council
- Victorian Government
- Natural Sciences and Engineering Research Council
- Canadian Institutes of Health Research
- Melbourne University
- St. Vincent's Institute of Medical Research
- Canadian Diabetes Association
- McMaster University
- Danish Medical Research Council
- Lundbeck Research Foundation
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AMP-activated protein kinase (AMPK) beta 1 or beta 2 subunits are required for assembling of AMPK heterotrimers and are important for regulating enzyme activity and cellular localization. In skeletal muscle, alpha 2 beta 2 gamma 3-containing heterotrimers predominate. However, compensatory up-regulation and redundancy of AMPK subunits in whole-body AMPK alpha 2, beta 2, and gamma 3 null mice has made it difficult to determine the physiological importance of AMPK in regulating muscle metabolism, because these models have normal mitochondrial content, contraction-stimulated glucose uptake, and insulin sensitivity. In the current study, we generated mice lacking both AMPK beta 1 and beta 2 isoforms in skeletal muscle (beta 1 beta 2M-KO). beta 1 beta 2M-KO mice are physically inactive and have a drastically impaired capacity for treadmill running that is associated with reductions in skeletal muscle mitochondrial content but not a fiber-type switch. Interestingly, young beta 1 beta 2M-KO mice fed a control chow diet are not obese or insulin resistant but do have impaired contraction-stimulated glucose uptake. These data demonstrate an obligatory role for skeletal muscle AMPK in maintaining mitochondrial capacity and contraction-stimulated glucose uptake, findings that were not apparent in mice with single mutations or deletions in muscle alpha, beta, or gamma subunits.
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