TWEAK promotes exercise intolerance by decreasing skeletal muscle oxidative phosphorylation capacity

Skeletal Muscle

Volumn 3, Issue 1, 2013, Pages

  Sato, Shuichi ^a   Ogura, Yuji ^a   Mishra, Vivek ^a,b   Shin, Jonghyun ^a   Bhatnagar, Shephali ^a   Hill, Bradford G ^a   Kumar, Ashok ^a  

^a University of Louisville School of Medicine   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

Exercise tolerance; Fn14; PGC 1 ; PPAR ; Skeletal muscle; TWEAK

Indexed keywords

MUS;

EID: 84879818423     PISSN: None     EISSN: 20445040     Source Type: Journal    
DOI: 10.1186/2044-5040-3-18     Document Type: Article

References (79)

1. Pette D. The adaptive potential of skeletal muscle fibers. Can J Appl Physiol 2002, 27:423-448. 10.1139/h02-023, 12442355.
2. Holloszy JO. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem 1967, 242:2278-2282.
3. Lanza IR, Sreekumaran Nair K. Regulation of skeletal muscle mitochondrial function: genes to proteins. Acta Physiol (Oxf) 2010, 199:529-547.
4. Arany Z. PGC-1 coactivators and skeletal muscle adaptations in health and disease. Curr Opin Genet Dev 2008, 18:426-434. 10.1016/j.gde.2008.07.018, 2629557, 18782618.
5. Finck BN, Kelly DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest 2006, 116:615-622. 10.1172/JCI27794, 1386111, 16511594.
6. Uldry M, Yang W, St-Pierre J, Lin J, Seale P, Spiegelman BM. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab 2006, 3:333-341. 10.1016/j.cmet.2006.04.002, 16679291.
7. Arany Z, Lebrasseur N, Morris C, Smith E, Yang W, Ma Y, Chin S, Spiegelman BM. The transcriptional coactivator PGC-1beta drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab 2007, 5:35-46. 10.1016/j.cmet.2006.12.003, 17189205.
8. Calvo JA, Daniels TG, Wang X, Paul A, Lin J, Spiegelman BM, Stevenson SC, Rangwala SM. Muscle-specific expression of PPARgamma coactivator-1alpha improves exercise performance and increases peak oxygen uptake. J Appl Physiol 2008, 104:1304-1312. 10.1152/japplphysiol.01231.2007, 18239076.
9. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 2002, 418:797-801. 10.1038/nature00904, 12181572.
10. Wende AR, Schaeffer PJ, Parker GJ, Zechner C, Han DH, Chen MM, Hancock CR, Lehman JJ, Huss JM, McClain DA, Holloszy JO, Kelly DP. A role for the transcriptional coactivator PGC-1alpha in muscle refueling. J Biol Chem 2007, 282:36642-36651. 10.1074/jbc.M707006200, 17932032.
11. Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, Goldberg AL, Spiegelman BM. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A 2006, 103:16260-16265. 10.1073/pnas.0607795103, 1637570, 17053067.
12. Brault JJ, Jespersen JG, Goldberg AL. Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. J Biol Chem 2010, 285:19460-19471. 10.1074/jbc.M110.113092, 2885225, 20404331.
13. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999, 98:115-124. 10.1016/S0092-8674(00)80611-X, 10412986.
14. Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci USA 2004, 101:6570-6575. 10.1073/pnas.0401401101, 404086, 15100410.
15. Huss JM, Kopp RP, Kelly DP. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem 2002, 277:40265-40274. 10.1074/jbc.M206324200, 12181319.
16. Huss JM, Torra IP, Staels B, Giguere V, Kelly DP. Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol 2004, 24:9079-9091. 10.1128/MCB.24.20.9079-9091.2004, 517878, 15456881.
17. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998, 92:829-839. 10.1016/S0092-8674(00)81410-5, 9529258.
18. Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 2008, 88:611-638. 10.1152/physrev.00025.2007, 18391175.
19. Romanello V, Guadagnin E, Gomes L, Roder I, Sandri C, Petersen Y, Milan G, Masiero E, Del Piccolo P, Foretz M, Scorrano L, Rudolf R, Sandri M. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J 2010, 29:1774-1785. 10.1038/emboj.2010.60, 2876965, 20400940.
20. Lokireddy S, Wijesoma IW, Teng S, Bonala S, Gluckman PD, McFarlane C, Sharma M, Kambadur R. The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell Metab 2012, 16:613-624. 10.1016/j.cmet.2012.10.005, 23140641.
21. Argiles JM, Busquets S, Toledo M, Lopez-Soriano FJ. The role of cytokines in cancer cachexia. Curr Opin Support Palliat Care 2009, 3:263-268. 10.1097/SPC.0b013e3283311d09, 19713854.
22. Carson JA, Baltgalvis KA. Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc Sport Sci Rev 2010, 38:168-176. 10.1097/JES.0b013e3181f44f11, 3065300, 20871233.
23. Hardin BJ, Campbell KS, Smith JD, Arbogast S, Smith J, Moylan JS, Reid MB. TNF-alpha acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle. J Appl Physiol 2008, 104:694-699. 10.1152/japplphysiol.00898.2007, 18187611.
24. Reid MB, Lannergren J, Westerblad H. Respiratory and limb muscle weakness induced by tumor necrosis factor-alpha: involvement of muscle myofilaments. Am J Respir Crit Care Med 2002, 166:479-484. 10.1164/rccm.2202005, 12186824.
25. Li YP, Schwartz RJ, Waddell ID, Holloway BR, Reid MB. Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha. FASEB J 1998, 12:871-880.
26. Li YP, Reid MB. NF-kappaB mediates the protein loss induced by TNF-alpha in differentiated skeletal muscle myotubes. Am J Physiol Regul Integr Comp Physiol 2000, 279:R1165-R1170.
27. Reid MB, Moylan JS. Beyond atrophy: redox mechanisms of muscle dysfunction in chronic inflammatory disease. J Physiol 2011, 589:2171-2179. 10.1113/jphysiol.2010.203356, 3098696, 21320886.
28. Romanatto T, Roman EA, Arruda AP, Denis RG, Solon C, Milanski M, Moraes JC, Bonfleur ML, Degasperi GR, Picardi PK, Hirabara S, Boschero AC, Curi R, Velloso LA. Deletion of tumor necrosis factor-alpha receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis. J Biol Chem 2009, 284:36213-36222. 10.1074/jbc.M109.030874, 2794737, 19858212.
29. Tang K, Wagner PD, Breen EC. TNF-alpha-mediated reduction in PGC-1alpha may impair skeletal muscle function after cigarette smoke exposure. J Cell Physiol 2010, 222:320-327. 10.1002/jcp.21955, 19859910.
30. White JP, Puppa MJ, Sato S, Gao S, Price RL, Baynes JW, Kostek MC, Matesic LE, Carson JA. IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the ApcMin/+ mouse. Skelet Muscle 2012, 2:14. 10.1186/2044-5040-2-14, 3431229, 22769563.
31. White JP, Baltgalvis KA, Puppa MJ, Sato S, Baynes JW, Carson JA. Muscle oxidative capacity during IL-6-dependent cancer cachexia. Am J Physiol Regul Integr Comp Physiol 2011, 300:R201-R211. 10.1152/ajpregu.00300.2010, 3043802, 21148472.
32. Mangner N, Linke A, Oberbach A, Kullnick Y, Gielen S, Sandri M, Hoellriegel R, Matsumoto Y, Schuler G, Adams V. Exercise training prevents TNF-alpha induced loss of force in the diaphragm of mice. PLoS One 2013, 8:e52274. 10.1371/journal.pone.0052274, 3534708, 23300968.
33. Santos RV, Viana VA, Boscolo RA, Marques VG, Santana MG, Lira FS, Tufik S, de Mello MT. Moderate exercise training modulates cytokine profile and sleep in elderly people. Cytokine 2012, 60:731-735. 10.1016/j.cyto.2012.07.028, 22917967.
34. Rubin DA, Hackney AC. Inflammatory cytokines and metabolic risk factors during growth and maturation: influence of physical activity. Med Sport Sci 2010, 55:43-55.
35. Christiansen T, Bruun JM, Paulsen SK, Olholm J, Overgaard K, Pedersen SB, Richelsen B. Acute exercise increases circulating inflammatory markers in overweight and obese compared with lean subjects. Eur J Appl Physiol 2013, 113:1635-1642. 10.1007/s00421-013-2592-0, 23361845.
36. Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, Garcia I, Browning JL. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J Biol Chem 1997, 272:32401-32410. 10.1074/jbc.272.51.32401, 9405449.
37. Meighan-Mantha RL, Hsu DK, Guo Y, Brown SA, Feng SL, Peifley KA, Alberts GF, Copeland NG, Gilbert DJ, Jenkins NA, Richards CM, Winkles JA. The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration. J Biol Chem 1999, 274:33166-33176. 10.1074/jbc.274.46.33166, 10551889.
38. Winkles JA, Tran NL, Brown SA, Stains N, Cunliffe HE, Berens ME. Role of TWEAK and Fn14 in tumor biology. Front Biosci 2007, 12:2761-2771. 10.2741/2270, 17127278.
39. Wiley SR, Cassiano L, Lofton T, Davis-Smith T, Winkles JA, Lindner V, Liu H, Daniel TO, Smith CA, Fanslow WC. A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity 2001, 15:837-846. 10.1016/S1074-7613(01)00232-1, 11728344.
40. Maecker H, Varfolomeev E, Kischkel F, Lawrence D, LeBlanc H, Lee W, Hurst S, Danilenko D, Li J, Filvaroff E, Yang B, Daniel D, Ashkenazi A. TWEAK attenuates the transition from innate to adaptive immunity. Cell 2005, 123:931-944. 10.1016/j.cell.2005.09.022, 16325585.
41. Mittal A, Bhatnagar S, Kumar A, Lach-Trifilieff E, Wauters S, Li H, Makonchuk DY, Glass DJ, Kumar A. The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice. J Cell Biol 2010, 188:833-849. 10.1083/jcb.200909117, 2845082, 20308426.
42. Kumar A, Bhatnagar S, Paul PK. TWEAK and TRAF6 regulate skeletal muscle atrophy. Curr Opin Clin Nutr Metab Care 2012, 15:233-239. 10.1097/MCO.0b013e328351c3fc, 3397822, 22366923.
43. Dahiya S, Bhatnagar S, Hindi SM, Jiang C, Paul PK, Kuang S, Kumar A. Elevated levels of active matrix metalloproteinase-9 cause hypertrophy in skeletal muscle of normal and dystrophin-deficient mdx mice. Hum Mol Genet 2011, 20:4345-4359. 10.1093/hmg/ddr362, 3196885, 21846793.
44. Safdar A, Little JP, Stokl AJ, Hettinga BP, Akhtar M, Tarnopolsky MA. Exercise increases mitochondrial PGC-1alpha content and promotes nuclear-mitochondrial cross-talk to coordinate mitochondrial biogenesis. J Biol Chem 2011, 286:10605-10617. 10.1074/jbc.M110.211466, 3060512, 21245132.
45. Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur NK, Yan Z, Spiegelman BM. Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J Biol Chem 2007, 282:30014-30021. 10.1074/jbc.M704817200, 17702743.
46. Nachlas MM, Tsou KC, De Souza E, Cheng CS, Seligman AM. Cytochemical demonstration of succinic dehydrogenase by the use of a new p-nitrophenyl substituted ditetrazole. J Histochem Cytochem 1957, 5:420-436. 10.1177/5.4.420, 13463314.
47. Sauerbeck A, Pandya J, Singh I, Bittman K, Readnower R, Bing G, Sullivan P. Analysis of regional brain mitochondrial bioenergetics and susceptibility to mitochondrial inhibition utilizing a microplate based system. J Neurosci Methods 2011, 198:36-43. 10.1016/j.jneumeth.2011.03.007, 3535268, 21402103.
48. Hill BG, Dranka BP, Zou L, Chatham JC, Darley-Usmar VM. Importance of the bioenergetic reserve capacity in response to cardiomyocyte stress induced by 4-hydroxynonenal. Biochem J 2009, 424:99-107. 10.1042/BJ20090934, 2872628, 19740075.
49. Dranka BP, Hill BG, Darley-Usmar VM. Mitochondrial reserve capacity in endothelial cells: the impact of nitric oxide and reactive oxygen species. Free Radic Biol Med 2010, 48:905-914. 10.1016/j.freeradbiomed.2010.01.015, 2860730, 20093177.
50. Perez J, Hill BG, Benavides GA, Dranka BP, Darley-Usmar VM. Role of cellular bioenergetics in smooth muscle cell proliferation induced by platelet-derived growth factor. Biochem J 2010, 428:255-267. 10.1042/BJ20100090, 3641000, 20331438.
51. Hill BG, Benavides GA, Lancaster JR, Ballinger S, Dell'italia L, Zhang J, Darley-Usmar VM. Integration of cellular bioenergetics with mitochondrial quality control and autophagy. Biol Chem 2012, 393:1485-1512. 3594552, 23092819.
52. Tadaishi M, Miura S, Kai Y, Kano Y, Oishi Y, Ezaki O. Skeletal muscle-specific expression of PGC-1alpha-b, an exercise-responsive isoform, increases exercise capacity and peak oxygen uptake. PLoS One 2011, 6:e28290. 10.1371/journal.pone.0028290, 3234261, 22174785.
53. Panguluri SK, Bhatnagar S, Kumar A, McCarthy JJ, Srivastava AK, Cooper NG, Lundy RF. Genomic profiling of messenger RNAs and microRNAs reveals potential mechanisms of TWEAK-induced skeletal muscle wasting in mice. PLoS One 2010, 5:e8760. 10.1371/journal.pone.0008760, 2808241, 20098732.
54. Vega RB, Huss JM, Kelly DP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 2000, 20:1868-1876. 10.1128/MCB.20.5.1868-1876.2000, 85369, 10669761.
55. Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ 2006, 30:145-151. 10.1152/advan.00052.2006, 17108241.
56. Chinsomboon J, Ruas J, Gupta RK, Thom R, Shoag J, Rowe GC, Sawada N, Raghuram S, Arany Z. The transcriptional coactivator PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle. Proc Natl Acad Sci U S A 2009, 106:21401-21406. 10.1073/pnas.0909131106, 2795492, 19966219.
57. Mortensen OH, Frandsen L, Schjerling P, Nishimura E, Grunnet N. PGC-1alpha and PGC-1beta have both similar and distinct effects on myofiber switching toward an oxidative phenotype. Am J Physiol Endocrinol Metab 2006, 291:E807-E816. 10.1152/ajpendo.00591.2005, 16720625.
58. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 2005, 3:e101. 10.1371/journal.pbio.0030101, 1064854, 15760270.
59. Shi J, Jiang B, Qiu Y, Guan J, Jain M, Cao X, Bauer M, Su L, Burkly LC, Leone TC, Kelly DP, Liao R. PGC1alpha plays a critical role in TWEAK-induced cardiac dysfunction. PLoS One 2013, 8:e54054. 10.1371/journal.pone.0054054, 3546975, 23342071.
60. Kliewer SA, Xu HE, Lambert MH, Willson TM. Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog Horm Res 2001, 56:239-263. 10.1210/rp.56.1.239, 11237216.
61. Takahashi S, Tanaka T, Sakai J. New therapeutic target for metabolic syndrome: PPARdelta. Endocr J 2007, 54:347-357. 10.1507/endocrj.KR-99, 17409576.
62. Fredenrich A, Grimaldi PA. PPAR delta: an uncompletely known nuclear receptor. Diabetes Metab 2005, 31:23-27. 10.1016/S1262-3636(07)70162-3, 15803109.
63. Muoio DM, MacLean PS, Lang DB, Li S, Houmard JA, Way JM, Winegar DA, Corton JC, Dohm GL, Kraus WE. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. J Biol Chem 2002, 277:26089-26097. 10.1074/jbc.M203997200, 12118038.
64. Holst D, Luquet S, Nogueira V, Kristiansen K, Leverve X, Grimaldi PA. Nutritional regulation and role of peroxisome proliferator-activated receptor delta in fatty acid catabolism in skeletal muscle. Biochim Biophys Acta 2003, 1633:43-50. 10.1016/S1388-1981(03)00071-4, 12842194.
65. Luquet S, Lopez-Soriano J, Holst D, Fredenrich A, Melki J, Rassoulzadegan M, Grimaldi PA. Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. FASEB J 2003, 17:2299-2301.
66. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham J, Kang H, Evans RM. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol 2004, 2:e294. 10.1371/journal.pbio.0020294, 509410, 15328533.
67. Hawley JA, Brouns F, Jeukendrup A. Strategies to enhance fat utilisation during exercise. Sports Med 1998, 25:241-257. 10.2165/00007256-199825040-00003, 9587182.
68. Helge JW. Long-term fat diet adaptation effects on performance, training capacity, and fat utilization. Med Sci Sports Exerc 2002, 34:1499-1504. 10.1097/00005768-200209000-00016, 12218745.
69. Miller WC, Bryce GR, Conlee RK. Adaptations to a high-fat diet that increase exercise endurance in male rats. J Appl Physiol 1984, 56:78-83.
70. Haramizu S, Nagasawa A, Ota N, Hase T, Tokimitsu I, Murase T. Different contribution of muscle and liver lipid metabolism to endurance capacity and obesity susceptibility of mice. J Appl Physiol 2009, 106:871-879. 10.1152/japplphysiol.90804.2008, 19131482.
71. Rodriguez-Calvo R, Serrano L, Coll T, Moullan N, Sanchez RM, Merlos M, Palomer X, Laguna JC, Michalik L, Wahli W, Vazquez-Carrera M. Activation of peroxisome proliferator-activated receptor beta/delta inhibits lipopolysaccharide-induced cytokine production in adipocytes by lowering nuclear factor-kappaB activity via extracellular signal-related kinase 1/2. Diabetes 2008, 57:2149-2157. 10.2337/db08-0176, 2494695, 18443198.
72. Serrano-Marco L, Chacon MR, Maymo-Masip E, Barroso E, Salvado L, Wabitsch M, Garrido-Sanchez L, Tinahones FJ, Palomer X, Vendrell J, Vazquez-Carrera M. TNF-alpha inhibits PPARbeta/delta activity and SIRT1 expression through NF-kappaB in human adipocytes. Biochim Biophys Acta 2012, 1821:1177-1185. 10.1016/j.bbalip.2012.05.006, 22683888.
73. Valerio A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, Palomba L, Cantoni O, Clementi E, Moncada S, Carruba MO, Nisoli E. TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. J Clin Invest 2006, 116:2791-2798. 1564431, 16981010.
74. Bhatnagar S, Mittal A, Gupta SK, Kumar A. TWEAK causes myotube atrophy through coordinated activation of ubiquitin-proteasome system, autophagy, and caspases. J Cell Physiol 2012, 227:1042-1051. 10.1002/jcp.22821, 21567392.
75. Paul PK, Gupta SK, Bhatnagar S, Panguluri SK, Darnay BG, Choi Y, Kumar A. Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice. J Cell Biol 2010, 191:1395-1411. 10.1083/jcb.201006098, 3010064, 21187332.
76. Kleiner S, Nguyen-Tran V, Bare O, Huang X, Spiegelman B, Wu Z. PPAR{delta} agonism activates fatty acid oxidation via PGC-1{alpha} but does not increase mitochondrial gene expression and function. J Biol Chem 2009, 284:18624-18633. 10.1074/jbc.M109.008797, 2707195, 19435887.
77. Dressel U, Allen TL, Pippal JB, Rohde PR, Lau P, Muscat GE. The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol Endocrinol 2003, 17:2477-2493. 10.1210/me.2003-0151, 14525954.
78. Piqueras L, Reynolds AR, Hodivala-Dilke KM, Alfranca A, Redondo JM, Hatae T, Tanabe T, Warner TD, Bishop-Bailey D. Activation of PPARbeta/delta induces endothelial cell proliferation and angiogenesis. Arterioscler Thromb Vasc Biol 2007, 27:63-69. 10.1161/01.ATV.0000250972.83623.61, 17068288.
79. Stephen RL, Gustafsson MC, Jarvis M, Tatoud R, Marshall BR, Knight D, Ehrenborg E, Harris AL, Wolf CR, Palmer CN. Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines. Cancer Res 2004, 64:3162-3170. 10.1158/0008-5472.CAN-03-2760, 15126355.