PMID- 23045346 OWN - NLM STAT- MEDLINE DCOM- 20130613 LR - 20220129 IS - 1469-7793 (Electronic) IS - 0022-3751 (Print) IS - 0022-3751 (Linking) VI - 590 IP - 24 DP - 2012 Dec 15 TI - Pharmacological activation of the pyruvate dehydrogenase complex reduces statin-mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents. PG - 6389-402 LID - 10.1113/jphysiol.2012.238022 [doi] AB - We previously reported that statin myopathy is associated with impaired carbohydrate (CHO) oxidation in fast-twitch rodent skeletal muscle, which we hypothesised occurred as a result of forkhead box protein O1 (FOXO1) mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) gene transcription. Upregulation of FOXO gene targets known to regulate proteasomal and lysosomal muscle protein breakdown was also evident. We hypothesised that increasing CHO oxidation in vivo, using the pyruvate dehydrogenase complex (PDC) activator, dichloroacetate (DCA), would blunt activation of FOXO gene targets and reduce statin myopathy. Female Wistar Hanover rats were dosed daily for 12 days (oral gavage) with either vehicle (control, 0.5% w/v hydroxypropyl-methylcellulose 0.1% w/v polysorbate-80; n = 9), 88 mg( )kg(-1) day(-1) simvastatin (n = 8), 88 mg( )kg(-1) day(-1) simvastatin + 30 mg kg(-1) day(-1) DCA (n = 9) or 88 mg kg(-1) day(-1) simvastatin + 40 mg kg(-1) day(-1) DCA (n = 9). Compared with control, simvastatin reduced body mass gain and food intake, increased muscle fibre necrosis, plasma creatine kinase levels, muscle PDK4, muscle atrophy F-box (MAFbx) and cathepsin-L mRNA expression, increased PDK4 protein expression, and proteasome and cathepsin-L activity, and reduced muscle PDC activity. Simvastatin with DCA maintained body mass gain and food intake, abrogated the myopathy, decreased muscle PDK4 mRNA and protein, MAFbx and cathepsin-L mRNA, increased activity of PDC and reduced proteasome activity compared with simvastatin. PDC activation abolished statin myopathy in rodent skeletal muscle, which occurred at least in part via inhibition of FOXO-mediated transcription of genes regulating muscle CHO utilisation and protein breakdown. FAU - Mallinson, Joanne E AU - Mallinson JE AD - MRC/Arthritis Research UK Centre for Musculoskeletal Ageing Research, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. joanne.mallinson@nottingham.ac.uk FAU - Constantin-Teodosiu, Dumitru AU - Constantin-Teodosiu D FAU - Glaves, Philip D AU - Glaves PD FAU - Martin, Elizabeth A AU - Martin EA FAU - Davies, Wendy J AU - Davies WJ FAU - Westwood, F Russell AU - Westwood FR FAU - Sidaway, James E AU - Sidaway JE FAU - Greenhaff, Paul L AU - Greenhaff PL LA - eng GR - MR/K00414X/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20121008 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 RN - 0 (Enzyme Activators) RN - 0 (Forkhead Transcription Factors) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Muscle Proteins) RN - 0 (Pdk4 protein, rat) RN - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase) RN - 0 (Pyruvate Dehydrogenase Complex) RN - 0 (RNA, Messenger) RN - 6DH1W9VH8Q (Acetylcarnitine) RN - 9LSH52S3LQ (Dichloroacetic Acid) RN - AGG2FN16EV (Simvastatin) RN - EC 2.3.2.27 (Fbxo32 protein, rat) RN - EC 2.3.2.27 (SKP Cullin F-Box Protein Ligases) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 3.4.22.15 (Cathepsin L) RN - EC 3.4.22.15 (Ctsl protein, rat) SB - IM MH - Acetylcarnitine/metabolism MH - Animals MH - Body Weight/drug effects MH - Carbohydrate Metabolism/drug effects MH - Cathepsin L/genetics/metabolism MH - Cytoprotection MH - Dichloroacetic Acid/*pharmacology MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Eating/drug effects MH - Enzyme Activation MH - Enzyme Activators/*pharmacology MH - Female MH - Forkhead Transcription Factors/genetics/*metabolism MH - Gene Expression Regulation MH - *Hydroxymethylglutaryl-CoA Reductase Inhibitors MH - Muscle Proteins/genetics/metabolism MH - Muscle, Skeletal/*drug effects/enzymology/pathology MH - Muscular Diseases/chemically induced/enzymology/genetics/pathology/*prevention & control MH - Necrosis MH - Oxidation-Reduction MH - Protein Serine-Threonine Kinases/genetics/metabolism MH - Pyruvate Dehydrogenase Acetyl-Transferring Kinase MH - Pyruvate Dehydrogenase Complex/*metabolism MH - RNA, Messenger/metabolism MH - Rats MH - Rats, Wistar MH - SKP Cullin F-Box Protein Ligases/genetics/metabolism MH - *Simvastatin MH - Time Factors PMC - PMC3533200 EDAT- 2012/10/10 06:00 MHDA- 2013/06/14 06:00 PMCR- 2013/12/15 CRDT- 2012/10/10 06:00 PHST- 2012/10/10 06:00 [entrez] PHST- 2012/10/10 06:00 [pubmed] PHST- 2013/06/14 06:00 [medline] PHST- 2013/12/15 00:00 [pmc-release] AID - jphysiol.2012.238022 [pii] AID - 10.1113/jphysiol.2012.238022 [doi] PST - ppublish SO - J Physiol. 2012 Dec 15;590(24):6389-402. doi: 10.1113/jphysiol.2012.238022. Epub 2012 Oct 8.