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Title: Gain-of-Function R225W Mutation in Human AMPKγ3 Causing Increased Glycogen and Decreased Triglyceride in Skeletal Muscle

Journal Article · · PLoS ONE
 [1];  [2];  [3];  [1];  [4];  [5];  [3];  [2];  [1]
  1. Univ. of Ottawa, ON (Canada). Faculty of Medicine. Dept. of Biochemistry, Microbiology and Immunology
  2. Univ. of Ottawa, ON (Canada). Heart Inst. Division of Cardiology and Lipoprotein and Atherosclerosis Research Group
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
  5. Ottawa Hospital Weight Management Clinic, Ottawa, ON (Canada)
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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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Cited By (19)

Metabolic functions of AMPK: Aspects of structure and of natural mutations in the regulatory gamma subunits journal October 2010
Are cultured human myotubes far from home? journal June 2013
Localisation of AMPK γ subunits in cardiac and skeletal muscles journal September 2013
Skeletal muscle transcriptional profiles in two Italian beef breeds, Chianina and Maremmana, reveal breed specific variation journal February 2016
Muscle-specific deletion of Prkaa1 enhances skeletal muscle lipid accumulation in mice fed a high-fat diet journal December 2017
Exercise-stimulated glucose uptake — regulation and implications for glycaemic control journal October 2016
Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury journal February 2018
AMPK in skeletal muscle function and metabolism journal January 2018
AMPK in Health and Disease journal July 2009
Domestic animals as models for biomedical research journal October 2015
Transcript variant dictates Prkag2 cardiomyopathy? journal September 2012
Deconvoluting AMP-activated protein kinase (AMPK) adenine nucleotide binding and sensing journal June 2017
Muscle transcriptome analysis reveals molecular pathways and biomarkers involved in extreme ultimate pH and meat defect occurrence in chicken posted_content January 2017
SNP variation in the promoter of the PRKAG3gene and association with meat quality traits in pig journal July 2012
Identification of differentially expressed genes in chickens differing in muscle glycogen content and meat quality journal February 2011
EMG-Normalised Kinase Activation during Exercise Is Higher in Human Gastrocnemius Compared to Soleus Muscle journal February 2012
Enhanced Muscle Insulin Sensitivity After Contraction/Exercise Is Mediated by AMPK journal October 2016
Exploring Impact of Rare Variation in Systemic Lupus Erythematosus by a Genome Wide Imputation Approach journal February 2019
AMPK and Exercise: Glucose Uptake and Insulin Sensitivity journal January 2013

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