Pharmacological activation of the pyruvate dehydrogenase complex reduces statin-mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents

Journal of Physiology

Volumn 590, Issue 24, 2012, Pages 6389-6402

  Mallinson, Joanne E ^a   Constantin Teodosiu, Dumitru ^a   Glaves, Philip D ^b   Martin, Elizabeth A ^b   Davies, Wendy J ^b   Westwood, F Russell ^b   Sidaway, James E ^b   Greenhaff, Paul L ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^b ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLCARNITINE; ATROGIN 1; CARBOHYDRATE; CATHEPSIN L; CREATINE KINASE; DICHLOROACETIC ACID; HYDROXYPROPYLMETHYLCELLULOSE; MESSENGER RNA; POLYSORBATE; PROTEASOME; PYRUVATE DEHYDROGENASE KINASE 4; SIMVASTATIN; TRANSCRIPTION FACTOR FOXO;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; AUTOPHAGY; BIOACCUMULATION; CARBOHYDRATE METABOLISM; CATHEPSIN L GENE; CONTROLLED STUDY; CREATINE KINASE BLOOD LEVEL; DOSE RESPONSE; DRUG INDUCED DISEASE; DRUG MEGADOSE; DRUG SAFETY; ENZYME ACTIVATION; ENZYME ACTIVITY; FOOD INTAKE; FORKHEAD BOX PROTEIN GENE; GENE ACTIVATION; GENE EXPRESSION; GENE FUNCTION; GENE TARGETING; IN VIVO STUDY; MUSCLE ATROPHY; MUSCLE ATROPHY F BOX GENE; MUSCLE CELL; MUSCLE NECROSIS; MYOPATHY; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PYRUVATE DEHYDROGENASE KINASE 4 GENE; UPREGULATION; WEIGHT GAIN;

ACETYLCARNITINE; ANIMALS; BODY WEIGHT; CARBOHYDRATE METABOLISM; CATHEPSIN L; CYTOPROTECTION; DICHLOROACETIC ACID; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; EATING; ENZYME ACTIVATION; ENZYME ACTIVATORS; FEMALE; FORKHEAD TRANSCRIPTION FACTORS; GENE EXPRESSION REGULATION; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; MUSCLE PROTEINS; MUSCLE, SKELETAL; MUSCULAR DISEASES; NECROSIS; OXIDATION-REDUCTION; PROTEIN-SERINE-THREONINE KINASES; PYRUVATE DEHYDROGENASE COMPLEX; RATS; RATS, WISTAR; RNA, MESSENGER; SIMVASTATIN; SKP CULLIN F-BOX PROTEIN LIGASES; TIME FACTORS;

EID: 84871096430     PISSN: 00223751     EISSN: 14697793     Source Type: Journal    
DOI: 10.1113/jphysiol.2012.238022     Document Type: Article

References (76)

1. Araki M & Motojima K (2008). Hydrophobic statins induce autophagy in cultured human rhabdomyosarcoma cells. Biochem Biophys Res Commun 367, 462-467.
2. Armstrong RB & Phelps RO (1984). Muscle fiber type composition of the rat hindlimb. Am J Anat 171, 259-272.
3. Bergmeyer H (1983). Methods in Enzymatic Analysis. John Wiley.
4. Blough E, Dineen B & Esser K (1999). Extraction of nuclear proteins from striated skeletal muscle. Biotechniques 26, 202-206.
5. Bouitbir J, Charles AL, Rasseneur L, Dufour S, Piquard F, Geny B & Zoll J (2011). Atorvastatin treatment reduces exercise capacities in rats: involvement of mitochondrial impairments and oxidative stress. J Appl Physiol 111, 1477-1483.
6. Bowker-Kinley MM, Davis WI, Wu P, Harris RA & Popov KM (1998). Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J 329, 191-196.
7. Bruckert E, Hayem G, Dejager S, Yau C & Begaud B (2005). Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients - the PRIMO study. Cardiovasc Drugs Ther 19, 403-414.
8. Cederblad G, Carlin JI, Constantin-Teodosiu D, Harper P & Hultman E (1990). Radioisotopic assays of CoASH and carnitine and their acetylated forms in human skeletal muscle. Anal Biochem 185, 274-278.
9. Clark AS, Mitch WE, Goodman MN, Fagan JM, Goheer MA & Curnow RT (1987). Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle. J Clin Invest 79, 588-594.
10. Constantin D, Constantin-Teodosiu D, Layfield R, Tsintzas K, Bennett AJ & Greenhaff PL (2007). PPAR delta agonism induces a change in muscle fuel metabolism and activation of an atrophy programme, but does not impair mitochondrial function. J Physiol 583, 381-390.
11. Constantin D, McCullough J, Mahajan RP & Greenhaff PL (2011). Novel events in the molecular regulation of muscle mass in critically ill patients. J Physiol 589, 3883-3895.
12. Constantin-Teodosiu D, Baker DJ, Constantin D & Greenhaff PL (2009). PPARδ agonism inhibits skeletal muscle PDC activity, mitochondrial ATP production and force generation during prolonged contraction. J Physiol 587, 231-239.
13. Constantin-Teodosiu D, Cederblad G & Hultman E (1991). A sensitive radioisotopic assay of pyruvate dehydrogenase complex in human muscle tissue. Anal Biochem 198, 347-351.
14. Constantin-Teodosiu D, Cederblad G & Hultman E (1993). PDC activity and acetyl group accumulation in skeletal muscle during isometric contraction. J Appl Physiol 74, 1712-1718.
15. Constantin-Teodosiu D, Constantin D, Stephens F, Laithwaite D & Greenhaff PL (2012). The role of FOXO and PPAR transcription factors in diet-mediated inhibition of PDC activation and carbohydrate oxidation during exercise in humans and the role of pharmacological activation of PDC in overriding these changes. Diabetes 61, 1017-1024.
16. Constantin-Teodosiu D, Simpson EJ & Greenhaff PL (1999). The importance of pyruvate availability to PDC activation and anaplerosis in human skeletal muscle. Am J Physiol Endocrinol Metab 276, E472-E478.
17. Crossland H, Constantin-Teodosiu D, Gardiner SM, Constantin D & Greenhaff PL (2008). A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle. J Physiol 586, 5589-5600.
18. Curto N, Tremolizzo L, Mattavelli L, Piatti ML, Marzorati L, Guerra L, Grassi MG & Ferrarese C (2006). A case of Melas (A3243G) on chronic dichloroacetate treatment. Eur Neurol 55, 37-38.
19. Dawson SP, Arnold JE, Mayer NJ, Reynolds SE, Billett MA, Gordon C, Colleaux L, Kloetzel PM, Tanaka K & Mayer RJ (1995). Developmental changes of the 26 S proteasome in abdominal intersegmental muscles of Manduca sexta during programmed cell death. J Biol Chem 270, 1850-1858.
20. Deedwania P, Stone PH, Bairey Merz CN, Cosin-Aguilar J, Koylan N, Luo D, Ouyang P, Piotrowicz R, Schenck-Gustafsson K, Sellier P, Stein JH, Thompson PL & Tzivoni D (2007). Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease. Circulation 115, 700-707.
21. Denton RM, Randle PJ & Martin BR (1972). Stimulation by calcium ions of pyruvate dehydrogenase phosphate phosphatase. Biochem J 128, 161-163.
22. Dirks AJ & Jones KM (2006). Statin-induced apoptosis and skeletal myopathy. Am J Physiol Cell Physiol 291, C1208-C1212.
23. Ferrando AA, Tipton KD, Doyle D, Phillips SM, Cortiella J & Wolfe RR (1998). Testosterone injection stimulates net protein synthesis but not tissue amino acid transport. Am J Physiol Endocrinol Metab 275, E864-E871.
24. Furuyama T, Kitayama K, Yamashita H & Mori N (2003). Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem J 275, 365-371.
25. Galtier F, Mura T, Raynaud de Mauverger E, Chevassus H, Farret A, Gagnol JP, Costa F, Dupuy A, Petit P, Cristol JP, Mercier J & Lacampagne A (2012). Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers. Toxicol Appl Pharmacol 263, 281-286.
26. Goodman MN, Ruderman NB & Aoki TT (1978). Glucose and amino acid metabolism in perfused skeletal muscle. Effect of dichloroacetate. Diabetes 27, 1065-1074.
27. Grassi B, Hogan MC, Greenhaff PL, Hamann JJ, Kelley KM, Aschenbach WG, Constantin-Teodosiu D & Gladden LB (2002). Oxygen uptake on-kinetics in dog gastrocnemius in situ following activation of pyruvate dehydrogenase by dichloroacetate. J Physiol 538, 195-207.
28. Jahoor F, Shangraw RE, Miyoshi H, Wallfish H, Herndon DN & Wolfe RR (1989). Role of insulin and glucose oxidation in mediating the protein catabolism of burns and sepsis. Am J Physiol Endocrinol Metab 257, E323-E331.
29. Kurlemann G, Paetzke I, Moller H, Masur H, Schuierer G, Weglage J & Koch HG (1995). Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy. Eur J Pediatr 154, 928-932.
30. Kwak HB, Thalacker-Mercer A, Anderson EJ, Lin CT, Kane DA, Lee NS, Cortright RN, Bamman MM & Neufer PD (2012). Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes. Free Radic Biol Med 52, 198-207.
31. Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J, Price SR, Mitch WE & Goldberg AL (2004). Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J 18, 39-51.
32. Li J, Kato M & Chuang DT (2009). Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate. J Biol Chem 284, 34458-34467.
33. Mallinson J, Constantin-Teodosiu D, Sidaway J, Westwood FR & Greenhaff P (2009). Blunted Akt/FOXO signalling and activation of genes controlling atrophy and fuel use in statin myopathy. J Physiol 587, 219-230.
34. Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S & Sandri M (2007). FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6, 458-471.
35. Mates JM, Segura JA, Alonso FJ & Marquez J (2006). Pathways from glutamine to apoptosis. Front Biosci 11, 3164-3180.
36. Meijer AJ & Codogno P (2004). Regulation and role of autophagy in mammalian cells. Int J Biochem Cell Biol 36, 2445-2462.
37. Mori M, Yamagata T, Goto T, Saito S & Momoi MY (2004). Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS. Brain Dev 26, 453-458.
38. Motojima K & Seto K (2003). Fibrates and statins rapidly and synergistically induce pyruvate dehydrogenase kinase 4 mRNA in the liver and muscles of mice. Biol Pharm Bull 26, 954-958.
39. Mullen PJ, Zahno A, Lindinger P, Maseneni S, Felser A, Krahenbuhl S & Brecht K (2011). Susceptibility to simvastatin-induced toxicity is partly determined by mitochondrial respiration and phosphorylation state of Akt. Biochim Biophys Acta 1813, 2079-2087.
40. NICE. (2006). Cardiovascular Disease - Statins. Retrieved 25th April, 2008, from http://www.nice.org.uk.
41. Nichols GA & Koro CE (2007). Does statin therapy initiation increase the risk for myopathy? An observational study of 32, 225 diabetic and nondiabetic patients. Clin Ther 29, 1761-1770.
42. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD & England JD (2002). Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 137, 581-585.
43. Platz TA, Wilson JS, Kline JA, Rushing G, Parker JL, Moore EM & Southern FN (2007). The beneficial effects of dichloroacetate in acute limb ischemia. Mil Med 172, 628-633.
44. Prada PO, Hirabara SM, de Souza CT, Schenka AA, Zecchin HG, Vassallo J, Velloso LA, Carneiro E, Carvalheira JB, Curi R & Saad MJ (2007). L-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity. Diabetologia 50, 1949-1959.
45. Preiss D, Seshasai SRK, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJP, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N & Ray KK (2011). Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy. JAMA 305, 2556-2564.
46. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT & Glynn RJ (2008). Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359, 2195-2207.
47. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH & Goldberg AL (2004). Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117, 399-412.
48. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK & Ford I (2010). Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375, 735-742.
49. Shangraw RE, Jahoor F, Miyoshi H, Neff WA, Stuart CA, Herndon DN & Wolfe RR (1989). Differentiation between septic and postburn insulin resistance. Metabolism 38, 983-989.
50. Sharma LK, Fang H, Liu J, Vartak R, Deng J & Bai Y (2011). Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum Mol Genet 20, 4605-4616.
51. Sirvent P, Fabre O, Bordenave S, Hillaire-Buys D, Raynaud De Mauverger E, Lacampagne A & Mercier J (2012). Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins. Toxicol Appl Pharmacol 259, 263-268.
52. Spruijt L, Naviaux RK, McGowan KA, Nyhan WL, Sheean G, Haas RH & Barshop BA (2001). Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Muscle Nerve 24, 916-924.
53. Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL & Kerr DS (1997). Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child 77, 535-541.
54. Stacpoole PW, Henderson GN, Yan Z, Cornett R & James MO (1998). Pharmacokinetics, metabolism and toxicology of dichloroacetate. Drug Metab Rev 30, 499-539.
55. Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, Felitsyn NM, Gilmore RL, Greer M, Henderson GN, Hutson AD, Neiberger RE, O'Brien RG, Perkins LA, Quisling RG, Shroads AL, Shuster JJ, Silverstein JH, Theriaque DW & Valenstein E (2006). Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 117, 1519-1531.
56. Stacpoole PW, Lorenz AC, Thomas RG & Harman EM (1988). Dichloroacetate in the treatment of lactic acidosis. Ann Intern Med 108, 58-63.
57. Stacpoole PW, Moore GW & Kornhauser DM (1978). Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. N Engl J Med 298, 526-530.
58. Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD & Glass DJ (2004). The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14, 395-403.
59. Szasz G, Gruber W & Bernt E (1976). Creatine kinase in serum: 1. Determination of optimum reaction conditions. Clin Chem 22, 650-656.
60. Thompson PD, Clarkson P & Karas RH (2003). Statin associated myopathy. JAMA 289, 1681-1690.
61. Timmons JA, Gustafsson T, Sundberg CJ, Jansson E & Greenhaff PL (1998a). Muscle acetyl group availability is a major determinant of oxygen deficit in humans during submaximal exercise. Am J Physiol Endocrinol Metab 274, E377-E380.
62. Timmons JA, Gustafsson T, Sundberg CJ, Jansson E, Hultman E, Kaijser L, Chwalbinska-Moneta J, Constantin-Teodosiu D, Macdonald IA & Greenhaff PL (1998b). Substrate availability limits human skeletal muscle oxidative ATP regeneration at the onset of ischemic exercise. J Clin Invest 101, 79-85.
63. Timmons JA, Poucher SM, Constantin-Teodosiu D, Macdonald IA & Greenhaff PL (1998c). Regulation of skeletal muscle carbohydrate oxidation during steady-state contraction. Am J Physiol Regul Integr Comp Physiol 274, R1384-R1389.
64. Timmons JA, Poucher SM, Constantin-Teodosiu D, Worrall V, Macdonald IA & Greenhaff PL (1996). Increased acetyl group availability enhances contractile function of canine skeletal muscle during ischemia. J Clin Invest 97, 879-883.
65. van Meijl LE, Popeijus HE & Mensink RP (2010). Amino acids stimulate Akt phosphorylation, and reduce IL-8 production and NF-κB activity in HepG2 liver cells. Mol Nutr Food Res 54, 1568-1573.
66. Vary TC & Hazen S (1999). Sepsis alters pyruvate dehydrogenase kinase activity in skeletal muscle. Mol Cell Biochem 198, 113-118.
67. Vary TC, Siegel JH, Zechnich A, Tall BD, Morris JG, Placko R & Jawor D (1988). Pharmacological reversal of abnormal glucose regulation, BCAA utilization, and muscle catabolism in sepsis by dichloroacetate. J Trauma 28, 1301-1311.
68. Vaughan CJ & Gotto AM (2004). Update on statins 2003. Circulation 110, 886-892.
69. Wells PG, Moore GW, Rabin D, Wilkinson GR, Oates JA & Stacpoole PW (1980). Metabolic effects and pharmacokinetics of intravenously administered dichloroacetate in humans. Diabetologia 19, 109-113.
70. Westwood FR, Bigley A, Randall K, Marsden AM & Scott RC (2005). Statin-induced muscle necrosis in the rat: distribution, development and fibre selectivity. Toxicol Pathol 33, 246-257.
71. Westwood FR, Scott RC, Marsden AM, Bigley A & Randall K (2008). Rosuvastatin: characterization of induced myopathy in the rat. Toxicol Pathol 36, 345-352.
72. Whitehouse S, Cooper RH & Randle PJ (1974). Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. Biochem J 141, 761-774.
73. Whitehouse S & Randle PJ (1973). Activation of pyruvate dehydrogenase in perfused rat heart by dichloroacetate (Short Communication). Biochem J 134, 651-653.
74. Wieland OH (1983). The mammalian pyruvate dehydrogenase complex: structure and regulation. Rev Physiol Biochem Pharmacol 96, 123-170.
75. Wu P, Inskeep K, Bower-Kinley M, Popov K & Harris R (1999). Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes. Diabetes 48, 1593-1599.
76. Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH & Goldberg AL (2007). FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscles. Cell Metab 6, 472-483.