title: Pharmacological activation of the pyruvate dehydrogenase complex reduces statin-mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents.
abstract: 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.
authors.affiliation: 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
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Mallinson
authors.forename: Dumitru
authors.initials: D
authors.lastname: Constantin-Teodosiu
authors.forename: Philip D
authors.initials: PD
authors.lastname: Glaves
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Martin
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Davies
authors.forename: F Russell
authors.initials: FR
authors.lastname: Westwood
authors.forename: James E
authors.initials: JE
authors.lastname: Sidaway
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
mesh_terms: D000108:Acetylcarnitine / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D050260:Carbohydrate Metabolism / Q000187:drug effects; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009336:Necrosis; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin; D013997:Time Factors
chemical_list: D020536:Enzyme Activators; D051858:Forkhead Transcription Factors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009124:Muscle Proteins; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D000108:Acetylcarnitine; D003999:Dichloroacetic Acid; D019821:Simvastatin; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; D017346:Protein Serine-Threonine Kinases; D056668:Cathepsin L; C534280:Ctsl protein, rat