Gain-of-Function R225W Mutation in Human AMPKγ3 Causing Increased Glycogen and Decreased Triglyceride in Skeletal Muscle
- Univ. of Ottawa, ON (Canada). Faculty of Medicine. Dept. of Biochemistry, Microbiology and Immunology
- Univ. of Ottawa, ON (Canada). Heart Inst. Division of Cardiology and Lipoprotein and Atherosclerosis Research Group
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
- Ottawa Hospital Weight Management Clinic, Ottawa, ON (Canada)
Background. AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is evolutionarily conserved from yeast to mammals and functions to maintain cellular and whole body energy homeostasis. Studies in experimental animals demonstrate that activation of AMPK in skeletal muscle protects against insulin resistance, type 2 diabetes and obesity. The regulatory c3 subunit of AMPK is expressed exclusively in skeletal muscle; however, its importance in controlling overall AMPK activity is unknown. While evidence is emerging that gamma subunit mutations interfere specifically with AMP activation, there remains some controversy regarding the impact of gamma subunit mutations [1–3]. Here we report the first gain-offunction mutation in the muscle-specific regulatory c3 subunit in humans. Methods and Findings. We sequenced the exons and splice junctions of the AMPK c3 gene (PRKAG3) in 761 obese and 759 lean individuals, identifying 87 sequence variants including a novel R225W mutation in subjects from two unrelated families. The c3 R225W mutation is homologous in location to the c2R302Q mutation in patients with Wolf-Parkinson-White syndrome and to the c3R225Q mutation originally linked to an increase in muscle glycogen content in purebred Hampshire Rendement Napole (RN- ) pigs. We demonstrate in differentiated muscle satellite cells obtained from the vastus lateralis of R225W carriers that the mutation is associated with an approximate doubling of both basal and AMP-activated AMPK activities. Moreover, subjects bearing the R225W mutation exhibit a ,90% increase of skeletal muscle glycogen content and a ,30% decrease in intramuscular triglyceride (IMTG). Conclusions. We have identified for the first time a mutation in the skeletal muscle-specific regulatory c3 subunit of AMPK in humans. The c3R225W mutation has significant functional effects as demonstrated by increases in basal and AMP-activated AMPK activities, increased muscle glycogen and decreased IMTG. Overall, these findings are consistent with an important regulatory role for AMPK c3 in human muscle energy metabolism.
- Research Organization:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
- Grant/Contract Number:
- AC02-05CH11231
- OSTI ID:
- 1627335
- Journal Information:
- PLoS ONE, Vol. 2, Issue 9; ISSN 1932-6203
- Publisher:
- Public Library of ScienceCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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