Document Detail

A transcriptomic approach to search for novel phenotypic regulators in McArdle disease.
MedLine Citation:
PMID:  22347505     Owner:  NLM     Status:  MEDLINE    
McArdle disease is caused by lack of glycogen phosphorylase (GP) activity in skeletal muscle. Patients experience exercise intolerance, presenting as early fatigue and contractures. In this study, we investigated the effects produced by a lack of GP on several genes and proteins of skeletal muscle in McArdle patients. Muscle tissue of 35 patients and 7 healthy controls were used to identify abnormalities in the patients' transcriptomic profile using low-density arrays. Gene expression was analyzed for the influence of variables such as sex and clinical severity. Differences in protein expression were studied by immunoblotting and 2D electrophoresis analysis, and protein complexes were examined by two-dimensional, blue native gel electrophoresis (BN-PAGE). A number of genes including those encoding acetyl-coA carboxylase beta, m-cadherin, calpain III, creatine kinase, glycogen synthase (GS), and sarcoplasmic reticulum calcium ATPase 1 (SERCA1), were found to be downregulated in patients. Specifically, compared to controls, GS and SERCA1 proteins were reduced by 50% and 75% respectively; also, unphosphorylated GS and SERCA1 were highly downregulated. On BN-PAGE analysis, GP was present with GS in two muscle protein complexes. Our findings revealed some issues that could be important in understanding the physiological consequences of McArdle disease: (i) SERCA1 downregulation in patients could result in impaired calcium transport in type II (fast-twitch) muscle fibers, leading to early fatigability during exercise tasks involving type II fibers (which mostly use glycolytic metabolism), i.e. isometric exercise, lifting weights or intense dynamic exercise (stair climbing, bicycling, walking at a very brisk pace), (ii) GP and GS were found together in two protein complexes, which suggests a new regulatory mechanism in the activity of these glycogen enzymes.
Gisela Nogales-Gadea; Inés Consuegra-García; Juan C Rubio; Joaquin Arenas; Marc Cuadros; Yolanda Camara; Javier Torres-Torronteras; Carmen Fiuza-Luces; Alejandro Lucia; Miguel A Martín; Elena García-Arumí; Antoni L Andreu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-02-09
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-02-20     Completed Date:  2012-07-31     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e31718     Citation Subset:  IM    
Departament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autónoma de Barcelona, Barcelona, Spain.
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MeSH Terms
Case-Control Studies
Gene Expression Regulation
Glycogen Phosphorylase / analysis
Glycogen Storage Disease Type V / genetics*
Glycogen Synthase / analysis
Multiprotein Complexes / physiology
Muscle Fibers, Fast-Twitch
Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
Reg. No./Substance:
0/Multiprotein Complexes; EC 2.4.1.-/Glycogen Phosphorylase; EC Synthase; EC Reticulum Calcium-Transporting ATPases

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