The therapeutic potential of skeletal muscle plasticity in Duchenne muscular dystrophy: Phenotypic modifiers as pharmacologic targets

FASEB Journal

Volumn 28, Issue 2, 2014, Pages 548-568

  Ljubicic, Vladimir ^a   Burt, Matthew ^a   Jasmin, Bernard J ^a  

^a UNIVERSITY OF OTTAWA   (Canada)

Author keywords

AMPK; PGC 1 ; PPAR ; SIRT1; Utrophin A

Indexed keywords

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; 6,7 DIHYDRO 4 HYDROXY 3 (2' HYDROXY 1,1' BIPHENYL 4 YL) 6 OXOTHIENO[2,3 B]PYRIDINE 5 CARBONITRILE; BERBERINE; CALCINEURIN; GUANIDINOPROPIONIC ACID; HISTONE DEACETYLASE 5; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; METFORMIN; MITOCHONDRIAL TRANSCRIPTION FACTOR A; MYOD PROTEIN; NICOTINAMIDE ADENINE DINUCLEOTIDE; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; QUERCETIN; RECEPTOR INTERACTING PROTEIN 140; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE; RESVERATROL; SALICYLIC ACID; SIRTUIN 1; TRANSCRIPTION FACTOR E2F1; TRANSCRIPTION FACTOR NFAT; TRANSCRIPTION FACTOR NRF1; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; UTROPHIN; UTROPHIN A; [2 METHYL 4 [4 METHYL 2 (4 TRIFLUOROMETHYLPHENYL) 5 THIAZOLYLMETHYLTHIO]PHENOXY]ACETIC ACID;

AEROBIC METABOLISM; CLINICAL TRIAL (TOPIC); DUCHENNE MUSCULAR DYSTROPHY; ENDURANCE TRAINING; ENZYME ACTIVATION; ENZYME ACTIVITY; FATTY ACID OXIDATION; GENE REPRESSION; GLYCOLYSIS; HUMAN; META ANALYSIS (TOPIC); MUSCLE DEVELOPMENT; NONHUMAN; PHARMACOLOGICAL STIMULATION; PHENOTYPE; PHENOTYPIC PLASTICITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN TARGETING; REGULATORY MECHANISM; REVIEW; SKELETAL MUSCLE; SKELETAL MUSCLE PLASTICITY; AMPK; ANIMAL; MALE; METABOLISM; PATHOPHYSIOLOGY; PGC-1Α; PPARΒ/Δ; SIRT1; UTROPHIN A;

AMPK; PGC-1Α; PPARΒ/Δ; SIRT1; UTROPHIN A;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; HUMANS; MALE; MUSCLE, SKELETAL; MUSCULAR DYSTROPHY, DUCHENNE;

EID: 84897064754     PISSN: 08926638     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.13-238071     Document Type: Review

References (166)

1. Bushby, K., Finkel, R., Birnkrant, D. J., Case, L. E., Clemens, P. R., Cripe, L., Kaul, A., Kinnett, K., McDonald, C., Pandya, S., Poysky, J., Shapiro, F., Tomezsko, J., and Constantin, C. (2010) Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 9, 77-93
2. Bushby, K., Finkel, R., Birnkrant, D. J., Case, L. E., Clemens, P. R., Cripe, L., Kaul, A., Kinnett, K., McDonald, C., Pandya, S., Poysky, J., Shapiro, F., Tomezsko, J., and Constantin, C. (2010) Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 9, 177-189
3. Hoffman, E. P., Brown, R. H., and Kunkel, L. M. (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51, 919-928
4. Davies, K. E., and Nowak, K. J. (2006) Molecular mechanisms of muscular dystrophies: old and new players. Nat. Rev. Mol. Cell Biol. 7, 762-773
5. Ervasti, J. M., and Campbell, K. P. (1993) Dystrophin and the membrane skeleton. Curr. Opin. Cell Biol. 5, 82-87
6. Blake, D. J., Weir, A., Newey, S. E., and Davies, K. E. (2002) Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol. Rev. 82, 291-329
7. Markert, C. D., Ambrosio, F., Call, J. A., and Grange, R. W. (2011) Exercise and Duchenne muscular dystrophy: toward evidence-based exercise prescription. Muscle Nerve 43, 464-478
8. Egan, B., and Zierath, J. R. (2013) Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 17, 162-184
9. Webster, C., Silberstein, L., Hays, P., and Blau, M. (1988) Fast muscle fibers are preferentially affected in Duchenne muscular dystrophy. Cell 52, 503-513
10. Moens, P., Baatsen, P. H., and Maréchal, G. (1993) Increased susceptibility of EDL muscles from mdx mice to damage induced by contractions with stretch. J. Muscle Res. Cell Motil. 14, 446-451
11. Hoffman, E. P., Bronson, A., Levin, A. A., Takeda, S., Yokota, T., Baudy, A. R., and Connor, E. M. (2011) Restoring dystrophin expression in duchenne muscular dystrophy muscle progress in exon skipping and stop codon read through. Am. J. Pathol. 179, 12-22
12. Mendell, J. R., Rodino-Klapac, L., Sahenk, Z., Malik, V., Kaspar, B. K., Walker, C. M., and Clark, K. R. (2012) Gene therapy for muscular dystrophy: lessons learned and path forward. Neurosci. Lett. 527, 90-99
13. Pichavant, C., Aartsma-Rus, A., Clemens, P. R., Davies, K. E., Dickson, G., Takeda, S., Wilton, S. D., Wolff, J. A., Wooddell, C. I., Xiao, X., and Tremblay, J. P. (2011) Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Mol. Ther. 19, 830-840
14. Fairclough, R. J., Perkins, K. J., and Davies, K. E. (2012) Pharmacologically targeting the primary defect and downstream pathology in Duchenne muscular dystrophy. Curr. Gene Ther. 12, 206-244
15. Chin, E. R., Olson, E. N., Richardson, J. A., Yang, Q., Humphries, C., Shelton, J. M., Wu, H., Zhu, W., Bassel-Duby, R., and Williams, R. S. (1998) A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev. 12, 2499-2509
16. Bassel-Duby, R., and Olson, E. N. (2006) Signaling pathways in skeletal muscle remodeling. Annu. Rev. Biochem. 75, 19-37
17. Long, Y. C., and Zierath, J. R. (2008) Influence of AMPactivated protein kinase and calcineurin on metabolic networks in skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 295, E545-E552
18. Michel, R. N., Chin, E. R., Chakkalakal, J. V., Eibl, J. K., and Jasmin, B. J. (2007) Ca2+/calmodulin-based signalling in the regulation of the muscle fibre phenotype and its therapeutic potential via modulation of utrophin A and myostatin expression. Appl. Physiol. Nutr. Metab. 32, 921-929
19. Jiang, L. Q., Garcia-Roves, P. M., de Castro Barbosa, T. C., and Zierath, J. R. (2010) Constitutively active calcineurin in skeletal muscle increases endurance performance and mitochondrial respiratory capacity. Am. J. Physiol. Endocrinol. Metab. 298, E8-E16
20. Handschin, C., and Spiegelman, B. M. (2006) Peroxisome Proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr. Rev. 27, 728-735
21. Safdar, A., Little, J. P., Stokl, A. J., Hettinga, B. P., Akhtar, M., and Tarnopolsky, M. A. (2011) Exercise increases mitochondrial PGC-1alpha content and promotes nuclear-mitochondrial cross-talk to coordinate mitochondrial biogenesis. J. Biol. Chem. 286, 10605-10617
22. Lira, V. A., Benton, C. R., Yan, Z., and Bonen, A. (2010) PGC-1a regulation by exercise training and its influences on muscle function and insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 299, E145-E161
23. Handschin, C., Rhee, J., Lin, J., Tarr, P. T., and Spiegelman, B. M. (2003) An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1 alpha expression in muscle. Proc. Natl. Acad. Sci. U. S. A. 100, 7111-7116
24. Lin, J., Wu, H., Tarr, P. T., Zhang, C., Wu, Z., Boss, O., Michael, L. F., Puigserver, P., Isotani, E., Olson, E. N., Lowell, B. B., Bassel-Duby, R., and Spiegelman, B. M. (2002) Transcriptional co-activator PGC-1a drives the formation of slow-twitch muscle fibres. Nature 418, 797-801
25. Handschin, C., Chin, S., Li, P., Liu, F., Maratos-Flier, E., Lebrasseur, N. K., Yan, Z., and Spiegelman, B. M. (2007) Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J. Biol. Chem. 282, 30014-30021
26. Ehrenborg, E. W. A., and Krook, A. (2009) Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor d. Pharmacol. Rev. 61, 373-393
27. Wang, Y.-X., Zhang, C.-L., Yu, R. T., Cho, H. K., Nelson, M. C., Bayuga-Ocampo, C. R., Ham, J., Kang, H., and Evans, R. M. (2004) Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol. 2, e294
28. Gan, Z., Burkart-hartman, E. M., Han, D., Finck, B., Leone, T. C., Smith, E. Y., Ayala, J. E., Holloszy, J., and Kelly, D. P. (2011) The nuclear receptor PPAR b/d programs muscle glucose metabolism in cooperation with AMPK and MEF2. Genes Dev. 25, 2619-2630
29. Gaudel, C., Schwartz, C., Giordano, C., Abumrad, N. A., and Grimaldi, P. A. (2008) Pharmacological activation of PPAR B promotes rapid and calcineurin-dependent fiber remodeling and angiogenesis in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 295, E297-E304
30. Luquet, S., Lopez-Soriano, J., Holst, D., Fredenrich, A., Melki, J., Rassoulzadegan, M., and Grimaldi, P. A. (2003) Peroxisome proliferator-activated receptor controls muscle development and oxidative capability. FASEB J. 17, 2299-2301
31. Schuler, M., Ali, F., Chambon, C., Duteil, D., Bornert, J.-M., Tardivel, A., Desvergne, B., Wahli, W., Chambon, P., and Metzger, D. (2006) PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fibertype switching, obesity, and type 2 diabetes. Cell Metab. 4, 407-414
32. Dressel, U., Allen, T. L., Pippal, J. B., Rohde, P. R., Lau, P., and Muscat, G. E. O. (2003) 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. 17, 2477-2493
33. Kleiner, S., Nguyen-Tran, V., Baré, O., Huang, X., Spiegelman, B., and Wu, Z. (2009) PPARd agonism activates fatty acid oxidation via PGC-1a but does not increase mitochondrial gene expression and function. J. Biol. Chem. 284, 18624-18633
34. Seth, A., Steel, J. H., Nichol, D., Pocock, V., Kumaran, M. K., Fritah, A., Mobberley, M., Ryder, T. a, Rowlerson, A., Scott, J., Poutanen, M., White, R., and Parker, M. (2007) The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab. 6, 236-245
35. Yamamoto, H., Williams, E. G., Mouchiroud, L., Cantó, C., Fan, W., Downes, M., Héligon, C., Barish, G. D., Desvergne, B., Evans, R. M., Schoonjans, K., and Auwerx, J. (2011) NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell 147, 827-839
36. Witczak, C. A., Sharoff, C. G., and Goodyear, L. J. (2008) AMP-activated protein kinase in skeletal muscle: from structure and localization to its role as a master regulator of cellular metabolism. Cell. Mol. Life Sci. 65, 3737-3755
37. Hardie, D. G. (2011) Sensing of energy and nutrients by AMP-activated protein kinase. Am. J. Clin. Nutr. 93, 891S-896S
38. O'Neill, H. M., Holloway, G. P., and Steinberg, G. R. (2013) AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol. Cell. Endocrinol. 366, 135-151
39. Cantó, C., and Auwerx, J. (2010) AMP-activated protein kinase and its downstream transcriptional pathways. Cell. Mol. Life Sci. 67, 3407-3423
40. Krämer, D. K., Al-Khalili, L., Guigas, B., Leng, Y., Garcia-Roves, P. M., and Krook, A. (2007) Role of AMP kinase and PPARdelta in the regulation of lipid and glucose metabolism in human skeletal muscle. J. Biol. Chem. 282, 19313-19320
41. Narkar, V. A., Downes, M., Yu, R. T., Embler, E., Wang, Y.-X., Banayo, E., Mihaylova, M. M., Nelson, M. C., Zou, Y., Juguilon, H., Kang, H., Shaw, R. J., and Evans, R. M. (2008) AMPK and PPARdelta agonists are exercise mimetics. Cell 134, 405-415
42. Rockl, K. S., Hirshman, M. F., Brandauer, J., Fujii, N., Witters, L. A., and Goodyear, L. J. (2007) Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. Diabetes 56, 2062-2069
43. Garcia-Roves, P. M., Osler, M. E., Holmstro, M. H., and Zierath, J. R. (2008) Gain-of-function R225Q mutation in AMP-activated protein kinase g3 subunit increases mitochondrial bio-genesis in glycolytic skeletal muscle. J. Biol. Chem. 283, 35724-35734
44. Fritah, A., Steel, J. H., Parker, N., Nikolopoulou, E., Christian, M., Carling, D., and Parker, M. G. (2012) Absence of RIP140 reveals a pathway regulating glut4-dependent glucose uptake in oxidative skeletal muscle through UCP1-mediated activation of AMPK. PloS ONE 7, e32520
45. Williams, D. B., Sutherland, L. N., Bomhof, M. R., Basaraba, S. A. U., Thrush, A. B., Dyck, D. J., Field, C. J., and Wright, D. C. (2009) Muscle-specific differences in the response of mitochondrial proteins to beta-GPA feeding: an evaluation of potential mechanisms. Am. J. Physiol. Endocrinol. Metab. 296, E1400-E1408
46. Fujii, N., Seifert, M. M., Kane, E. M., Peter, L. E., Ho, R. C., Winstead, S., Hirshman, M. F., and Goodyear, L. J. (2007) Role of AMP-activated protein kinase in exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle: insight from analysis of a transgenic mouse model. Diabetes Res. Clin. Pract. Suppl. 77S, S92-S98
47. Jørgensen, S. B., Treebak, J. T., Viollet, B., Schjerling, P., Vaulont, S., Wojtaszewski, J. F. P., and Richter, E. A. (2007) Role of AMPKalpha2 in basal, training-, and AICAR-induced GLUT4, hexokinase II, and mitochondrial protein expression in mouse muscle. Am. J. Physiol. Endocrinol. Metab. 292, E331- E339
48. O'Neill, H. M., Maarbjerg, S. J., Crane, J. D., Jeppesen, J., and Jørgensen, S. B. (2011) AMP-activated protein kinase (AMPK) B1B2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc. Natl. Acad. Sci. U. S. A. 108, 16092-16097
49. Barré, L., Richardson, C., Hirshman, M. F., Brozinick, J., Fiering, S., Kemp, B. E., Goodyear, L. J., and Witters, L. A. (2007) Genetic model for the chronic activation of skeletal muscle AMP-activated protein kinase leads to glycogen accumulation. Am. J. Physiol. Endocrinol. Metab. 292, E802-E811
50. Baur, J. A., Ungvari, Z., Minor, R. K., Le Couteur, D. G., and de Cabo, R. (2012) Are sirtuins viable targets for improving healthspan and lifespan? Nat. Rev. Drug Discov. 11, 443-461
51. Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., Geny, B., Laakso, M., Puigserver, P., and Auwerx, J. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC- 1alpha. Cell 127, 1109-1122
52. Chung, S., Yao, H., Caito, S., Hwang, J., Arunachalam, G., and Rahman, I. (2010) Regulation of SIRT1 in cellular functions: Role of polyphenols. Arch. Biochem. Biophys. 501, 79-90
53. Gurd, B. J. (2011) Deacetylation of PGC-1 by SIRT1: importance for skeletal muscle function and exercise-induced mitochondrial biogenesis. Appl. Physiol. Nutr. Metab. 36, 589-597
54. Amat, R., Planavila, A., Chen, S. L., Iglesias, R., Giralt, M., and Villarroya, F. (2009) SIRT1 controls the transcription of the peroxisome proliferator-activated receptor-gamma co-activator- 1alpha (PGC-1alpha) gene in skeletal muscle through the PGC-1alpha autoregulatory loop and interaction with MyoD. J. Biol. Chem. 284, 21872-21880
55. Nemoto, S., Fergusson, M. M., and Finkel, T. (2004) Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 306, 2105-2108
56. Cantó, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., Elliott, P. J., Puigserver, P., and Auwerx, J. (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056-1060
57. Cantó, C., Jiang, L. Q., Deshmukh, A. S., Mataki, C., Coste, A., Lagouge, M., Zierath, J. R., and Auwerx, J. (2010) Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 11, 213-219
58. Gerhart-Hines, Z., Rodgers, J. T., Bare, O., Lerin, C., Kim, S.-H., Mostoslavsky, R., Alt, F. W., Wu, Z., and Puigserver, P. (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 26, 1913-1923
59. Schenk, S., Mccurdy, C. E., Philp, A., Chen, M. Z., Holliday, M. J., Bandyopadhyay, G. K., Osborn, O., Baar, K., and Olefsky, J. M. (2011) Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. J. Clin. Invest. 121, 4281-4288
60. Menzies, K. J., Singh, K., Saleem, A., and Hood, D. A. (2013) Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J. Biol. Chem. 288, 6968-6979
61. Philp, A., Chen, A., Lan, D., Meyer, G. A., Murphy, A. N., Knapp, A. E., Olfert, I. M., McCurdy, C. E., Marcotte, G. R., Hogan, M. C., Baar, K., and Schenk, S. (2011) Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptorgamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise. J. Biol. Chem. 286, 30561-30570
62. Gurd, B. J., Yoshida, Y., Lally, J., Holloway, G. P., and Bonen, A. (2009) The deacetylase enzyme SIRT1 is not associated with oxidative capacity in rat heart and skeletal muscle and its overexpression reduces mitochondrial biogenesis. J. Physiol. 587.8, 1817-1828
63. White, A. T., McCurdy, C. E., Philp, A., Hamilton, D. L., Johnson, C. D., and Schenk, S. (2013) Skeletal muscle-specific overexpression of SIRT1 does not enhance whole-body energy expenditure or insulin sensitivity in young mice. Diabetologia 56, 1629-1637
64. Hoshino, D., Yoshida, Y., Holloway, G. P., Lally, J., Hatta, H., and Bonen, A. (2012) Clenbuterol, a 2-adrenergic agonist, reciprocally alters PGC-1 alpha and RIP140 and reduces fatty acid and pyruvate oxidation in rat skeletal muscle RIP140 and reduces fatty acid and pyruvate oxidation in rat skeletal muscle. Am. J. Physiol. Regul. Integr. Comp Physiol. 302, R373-R384
65. Frier, B. C., Hancock, C. R., Little, J. P., Fillmore, N., Tyler, A., Thomson, D. M., Wan, Z., Wright, D. C., and Bliss, T. A. (2011) Reductions in RIP140 are not required for exercise- and AICAR-mediated increases in skeletal muscle mitochondrial content. J. Appl. Physiol. 111, 688-695
66. Hallberg, M., Morganstein, D. L., Kiskinis, E., Shah, K., Kralli, A., Dilworth, S. M., White, R., Parker, M. G., and Christian, M. (2008) A functional interaction between RIP140 and PGC- 1alpha regulates the expression of the lipid droplet protein CIDEA. Mol. Cell. Biol. 28, 6785-6795
67. Pérez-Schindler, J., Summermatter, S., Salatino, S., Zorzato, F., Beer, M., Balwierz, P. J., van Nimwegen, E., Feige, J. N., Auwerx, J., and Handschin, C. (2012) The corepressor NCoR1 antagonizes PGC-1 and estrogen-related receptor in the regulation of skeletal muscle function and oxidative metabolism. Mol. Cell. Biol. 32, 4913-4924
68. Perkins, K. J., Basu, U., Budak, M. T., Ketterer, C., Baby, S. M., Lozynska, O., Lunde, J. A., Jasmin, B. J., Rubinstein, N. A., and Khurana, T. S. (2007) Ets-2 repressor factor silences extrasynaptic utrophin by N-box-mediated repression in skeletal muscle. Mol. Biol. Cell 18, 2864-2872
69. Blanchet, E., Annicotte, J.-S., Lagarrigue, S., Aguilar, V., Clapé, C., Chavey, C., Fritz, V., Casas, F., Apparailly, F., Auwerx, J., and Fajas, L. (2011) E2F transcription factor-1 regulates oxidative metabolism. Nat. Cell Biol. 13, 1146-1152
70. Meng, Z.-X., Li, S., Wang, L., Ko, H. J., Lee, Y., Jung, D. Y., Okutsu, M., Yan, Z., Kim, J. K., and Lin, J. D. (2013) Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation. Nat. Med. 19, 640-645
71. Jucker, B. M., Yang, D., Casey, W. M., Olzinski, A. R., Williams, Lenhard, C., S.C., Legos, J. J., Hawk, C. T., Susanta, K., and Newsholme, S. J. (2007) Selective PPAR agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study. Am. J. Physiol. Endocrinol. Metab. 293, E1256-E1264
72. Tanaka, T., Yamamoto, J., Iwasaki, S., Asaba, H., Hamura, H., Ikeda, Y., Watanabe, M., Magoori, K., Ioka, R. X., Tachibana, K., Watanabe, Y., Uchiyama, Y., Sumi, K., Iguchi, H., Ito, S., Doi, T., Hamakubo, T., Naito, M., Auwerx, J., Yanagisawa, M., Kodoma, T., and Sakai, J. (2003) Activation of peroxisome proliferator-activated receptor d induces fatty acid B-oxidation in skeletal muscle and attenuates metaolic syndrome. Proc. Natl. Acad. Sci. U. S. A. 100, 15924-15929
73. Riserus, U., Sprecher, D., Johnson, T., Olson, E., Hirschberg, S., Liu, A., Fang, Z., Hegde, P., Richards, D., Sarov-Blat, L., Strum, J. C., Basu, S., Cheeseman, J., Fielding, B. A., Humphreys, S. M., Danoff, T., Moore, N. R., Murgatroyd, P., O'Rahilly, S., Sutton, P., Wilson, T., Hassall, D., Frayn, K. N., and Karpe, F. (2008) Activation of peroxisome proliferator-activated receptor (PPAR)d promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 57, 332-339
74. Olson, E. J., Pearce, G. L., Jones, N. P., and Sprecher, D. L. (2012) Lipid effects of peroxisome proliferator-activated receptor- β agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 32, 2289-2294
75. Bays, H. E., Schwartz, S., Littlejohn, T., Kerzner, B., Krauss, R. M., Karpf, D. B., Choi, Y.-J., Wang, X., Naim, S., and Roberts, B. K. (2011) MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J. Clin. Endocrinol. Metab. 96, 2889-2897
76. Winder, W. W., Holmes, B. F., Rubink, D. S., Jensen, E. B., Chen, M., and Holloszy, J. O. (2000) Activation of AMPactivated protein kinase increases mitochondrial enzymes in skeletal muscle. J. Appl. Physiol. 88, 2219-2226
77. Leick, L., Fentz, J., Biensø, R. S., Knudsen, J. G., Jeppesen, J., Kiens, B., Wojtaszewski, J. F. P., and Pilegaard, H. (2010) PGC-1a is required for AICAR-induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 299, E456-E465
78. Fillmore, N., Jacobs, D. L., Mills, D. B., Winder, W. W., and Hancock, C. R. (2010) Chronic AMP-activated protein kinase activation and a high-fat diet have an additive effect on mitochondria in rat skeletal muscle. J. Appl. Physiol. 109, 511-520
79. Pold, R., Jensen, L. S., Jessen, N., Buhl, E. S., Schmitz, O., Flyvbjerg, A., Fujii, N., Goodyear, L. J., Gotfredsen, C. F., Brand, C. L., and Lund, S. (2005) Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes 54, 928-934
80. Bergeron, R., Ren, J. M., Cadman, K. S., Moore, I. K., Perret, P., Pypaert, M., Young, L. H., Semenkovich, C. F., and Shulman, G. I. (2001) Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am. J. Physiol. Endocrinol. Metab. 281, E1340-E1346
81. Zong, H., Ren, J. M., Young, L. H., Pypaert, M., Mu, J., Birnbaum, M. J., and Shulman, G. I. (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc. Natl. Acad. Sci. U. S. A. 99, 15983-15987
82. Ren, J. M., Ohira, Y., Holloszy, J. O., Hämäläinen, N., Traub, I., and Pette, D. (1995) Effects of beta-guanidinopropionic acidfeeding on the patterns of myosin isoforms in rat fasttwitch muscle. Pflügers Arch. 430, 389-393
83. Musi, N., Hirshman, M. F., Nygren, J., Svanfeldt, M., Bavenholm, P., Rooyackers, O., Zhou, G., Williamson, J. M., Ljunqvist, O., Efendic, S., Moller, D. E., Thorell, A., and Goodyear, L. J. (2002) Metformin increases amp-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51, 2074-2081
84. Suwa, M., Egashira, T., Nakano, H., Sasaki, H., and Kumagai, S. (2006) Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo. J. Appl. Physiol. 101, 1685-1692
85. Price, N. L., Gomes, A. P., Ling, A. J. Y., Duarte, F. V., Martin-Montalvo, A., North, B. J., Agarwal, B., Ye, L., Ramadori, G., Teodoro, J. S., Hubbard, B. P., Varela, A. T., Davis, J. G., Varamini, B., Hafner, A., Moaddel, R., Rolo, A. P., Coppari, R., Palmiera, C. M., de Cabo, R., Baur, J. A., and Sinclair, D. A. (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15, 675-690
86. Park, C. E., Kim, M.-J., Lee, J. H., Min, B.-I., Bae, H., Choe, W., Kim, S.-S., and Ha, J. (2007) Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase. Exp. Mol. Med. 39, 222-229
87. Hawley, S. A., Ross, F. A., Chevtzoff, C., Green, K. A., Evans, A., Fogarty, S., Towler, M. C., Brown, L. J., Ogunbayo, O. A., Evans, A. M., and Hardie, D. G. (2010) Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554-565
88. Centeno-Baez, C., Dallaire, P., and Marette, A. (2011) Resveratrol inhibition of inducible nitric oxide synthase in skeletal muscle involves AMPK but not SIRT1. Am. J. Physiol. Endocrinol. Metab. 301, E922-E930
89. Breen, D. M., Sanli, T., Giacca, A., and Tsiani, E. (2008) Stimulation of muscle cell glucose uptake by resveratrol through sirtuins and AMPK. Biochem. Biophys. Res. Commun. 374, 117-122
90. Um, J., Park, S., Kang, H., Yang, S., Foretz, M., McBurney, M. W., Kim, M. K., Viollet, B., and Chung, J. H. (2010) AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59, 554-563
91. Dixon, R., Gourzis, J., Mcdermott, D., Fujitaki, J., Dewland, P., and Gruber, H. (1991) AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent. J. Clin. Pharmacol. 31, 342-347
92. Mangano, D. T., Miao, Y., Tudor, I. C., and Dietzel, C. (2006) Post-reperfusion myocardial infarction: long-term survival improvement using adenosine regulation with acadesine. J. Am. Coll. Cardiol. 48, 206-214
93. Drew, B. G., and Kingwell, B. A. (2008) Acadensine, an adenosine-regulating agent with the potential for widespread indications. Expert Opin. Pharmacother. 9, 2137-2144
94. Babraj, J. A., Mustard, K., Sutherland, C., Towler, M. C., Chen, S., Smith, K., Green, K., Leese, G., Hardie, D. G., Rennie, M. J., and Cuthbertson, D. J. (2009) Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status. Am. J. Physiol. Endocrinol. Metab. 296, E1042-E1048
95. Boon, H., Bosselaar, M., Praet, S. F. E., Blaak, E. E., Saris, W. H. M., Wagenmakersa, J. M., McGee, S. L., Tack, C. J., Smits, P., Hargreaves, M., and van Loon, L. J. C. (2008) Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients. Diabetologia 51, 1893-1900
96. Bosselaar, M., Smits, P., van Loon, L. J. C., and Tack, C. J. (2011) Intravenous AICAR during hyperinsulinemia induces systemic hemodynamic changes but has no local metabolic effect. J. Clin. Pharmacol. 51, 1449-1458
97. Cuthbertson, D. J., Babraj, J. A., Mustard, K. J. W., Towler, M. C., Green, K. A., Wackerhage, H., Leese, G. P., Baar, K., Thomason-Hughes, M., Sutherland, C., Hardie, D. G., and Rennie, M. J. (2007) 5-Aminoimidazole-4- carboxamide 1-B-dribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men. Diabetes 56, 2078-2084
98. Timmers, S., Auwerx, J., and Schrauwen, P. (2012) The journey of resveratrol from yeast to human. Aging 4, 146-158
99. Viollet, B., Guigas, B., Sanz Garcia, N., Leclerc, J., Foretz, M., and Andreelli, F. (2012) Cellular and molecular mechanisms of metformin: an overview. Clin. Sci. 122, 253-270
100. Hawley, S. A., Fullerton, M. D., Ross, F. A., Schertzer, J. D., Chevtzoff, C., Walker, K. J., Peggie, M. W., Zibrova, D., Green, K. A., Mustard, K. J., Kemp, B. E., Sakamoto, K., Steinberg, G. R., and Hardie, D. G. (2012) The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918-922
101. Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L.-L., Scherer, B., and Sinclair, D. A. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191-196
102. Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N., Swindell, W. R., Kamara, D., Minor, R. K., Perez, E., Jamieson, H. A., Zhang, Y., Dunn, S. R., Sharma, K., Pleshko, N., Wollett, L. A., Csiszar, A., Ikeno, Y., Le Couteur, D., Elliot, P. J., Becker, K. G., Navas, P., Ingram, D. K., Wolf, N. S., Ungvari, Z., Sinclair, D. A., and de Cabo, R. (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 8, 157-168
103. Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., Pistell, P. J., Poosala, S., Becker, K. G., Boss, O., Gwinn, D., Wang, M., Ramaswamy, S., Fishbein, K. W., Spencer, R. G., Lakatta, E. G., Le Couteur, D., Shaw, R. J., Navas, P., Puigserver, P., Ingram, D. K., de Cabo, R., and Sinclair, D. A. (2006) Resveratrol improves health and survival of mice on a highcalorie diet. Nature 444, 337-342
104. Momken, I., Stevens, L., Bergouignan, A., Desplanches, D., Rudwill, F., Chery, I., Zahariev, A., Zahn, S., Stein, T. P., Sebedio, J. L., Pujos-Guillot, E., Falempin, M., Simon, C., Coxam, V., Andrianjafiniony, T., Gauquelin-Koch, G., Picquet, F., and Blanc, S. (2011) Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. FASEB J. 25, 3646-3660
105. Dolinsky, V. W., Jones, K. E., Sidhu, R. S., Haykowsky, M., Czubryt, M. P., and Dyck, J. R. B. (2012) Improvements in skeletal muscle strength and cardiac function induced by resveratrol during exercise training contribute to enhanced exercise performance in rats. J. Physiol. 590.11, 2783-2799
106. Park, S.-J., Ahmad, F., Philp, A., Baar, K., Williams, T., Luo, H., Ke, H., Rehmann, H., Taussig, R., Brown, A. L., Kim, M. K., Beaven, M. A., Burgin, A. B., Manganiello, V., and Chung, J. H. (2012) Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148, 421-433
107. Milne, J. C., Lambert, P. D., Schenk, S., Carney, D. P., Smith, J. J., Gagne, D. J., Jin, L., Boss, O., Perni, R. B., Vu, C. B., Berris, J. E., Xiw, R., Disch, J. S., Ng, P. Y., Nunes, J. J., Lynch, A. V., Yang, H., Golonek, H., Israelian, K., Choy, W., Iffland, A., Lavu, S., Medvedik, O., Sinclair, D. A., Olefsky, J. M., Jirousek, M. R., Elliot, P. J., and Westphal, C. H. (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712-716
108. Feige, J. N., Lagouge, M., Canto, C., Strehle, A., Houten, S. M., Milne, J. C., Lambert, P. D., Mataki, C., Elliott, P. J., and Auwerx, J. (2008) Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 8, 347-358
109. Minor, R. K., Baur, J. A., Gomes, A. P., Ward, T. M., Csiszar, A., Mercken, E. M., Abdelmohsen, K., Shin, Y., Canto, C., Scheibye-Knudsen, M., Krawczyk, M., Irusta, P. M., Martin- Montalvo, A., Hubbar, B. P., Zhang, Y., Lehrmann, E., White, A. A., Price, N. L., Swindell, W. R., Pearson, K. J., Becker, K. G., Bohr, V. A., Gorospe, M., Egan, J. M., Talan, M. I., Auwerx, J., Westphal, C., H., Ellis, J. L., Ungvari, Z., Vlasuk, G. P., Elliot, P. J., Sinclair, D. A., and de Cabo, R. (2011) SRT1720 improves survival and healthspan of obese mice. Sci. Rep. 1, 1-10
110. Crandall, J. P., Oram, V., Trandafirescu, G., Reid, M., Kishore, P., Hawkins, M., Cohen, H. W., and Barzilai, N. (2012) Pilot study of resveratrol in older adults with impaired glucose tolerance. J. Gerontol. A. Biol. Sci. Med. Sci. 67, 1307-1312
111. Brasnyó, P., Molnár, G. A., Mohás, M., Markó, L., Laczy, B., Cseh, J., Mikolás, E., Szijártó, I. A., Mérei, A., Halmai, R., Mészáros, L. G., Sümegi, B., and Wittmann, I. (2011) Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br. J. Nutr. 106, 383-389
112. Yoshino, J., Conte, C., Fontana, L., Mittendorfer, B., Imai, S., Schechtman, K. B., Gu, C., Kunz, I., Rossi Fanelli, F., Patterson, B. W., and Klein, S. (2012) Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab. 16, 658-664
113. Angus, L. M., Chakkalakal, J. V., Méjat, A., Eibl, J. K., Bélanger, G., Megeney, L. A., Chin, E. R., Schaeffer, L., Michel, R. N., and Jasmin, B. J. (2005) Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1a, drives utrophin gene expression at the neuromuscular junction. Am. J. Physiol. Cell Physiol. 289, C908-C917
114. Chakkalakal, J. V., Harrison, M.-A., Carbonetto, S., Chin, E., Michel, R. N., and Jasmin, B. J. (2004) Stimulation of calcineurin signaling attenuates the dystrophic pathology in mdx mice. Hum. Mol. Genet. 13, 379-388
115. Chakkalakal, J. V., Michel, S. a, Chin, E. R., Michel, R. N., and Jasmin, B. J. (2006) Targeted inhibition of Ca2+/calmodulin signaling exacerbates the dystrophic phenotype in mdx mouse muscle. Hum. Mol. Genet. 15, 1423-1435
116. Chakkalakal, J. V., Stocksley, M. A., Harrison, M.-A., Angus, L. M., Deschenes-Furry, J., St-Pierre, S., Megeney, L. A., Chin, E. R., Michel, R. N., and Jasmin, B. J. (2003) Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/ NFAT signaling. Proc. Natl. Acad. Sci. U. S. A. 100, 7791-7796
117. Gramolini, A. O., Bélanger, G., Thompson, J. M., Chakkalakal, J. V., and Jasmin, B. J. (2001) Increased expression of utrophin in a slow vs. a fast muscle involves posttranscriptional events. Am. J. Physiol. Cell Physiol. 281, C1300-C1309
118. Ljubicic, V., and Jasmin, B. J. (2013) AMP-activated protein kinase at the nexus of therapeutic skeletal muscle plasticity in Duchenne muscular dystrophy. Trends Mol. Med. 19, 614-624
119. Ljubicic, V., Khogali, S., Renaud, J.-M., and Jasmin, B. J. (2012) Chronic AMPK stimulation attenuates adaptive signaling in dystrophic skeletal muscle. Am. J. Physiol. Cell Physiol. 302, C110-C121
120. Ljubicic, V., Miura, P., Burt, M., Boudreault, L., Khogali, S., Lunde, J. A., Renaud, J.-M., and Jasmin, B. J. (2011) Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle. Hum. Mol. Genet. 20, 3478-3493
121. Miura, P., Chakkalakal, J. V., Boudreault, L., Bélanger, G., Hébert, R. L., Renaud, J.-M., and Jasmin, B. J. (2009) Pharmacological activation of PPARbeta/delta stimulates utrophin A expression in skeletal muscle fibers and restores sarcolemmal integrity in mature mdx mice. Hum. Mol. Genet. 18, 4640-4649
122. Baltgalvis, K. A., Call, J. A., Cochrane, G. D., Laker, R. C., Yan, Z., and Lowe, D. A. (2012) Exercise training improves plantarflexor muscle function in mdx mice. Med. Sci. Sports Exerc. 44, 1671-1679
123. Blanchet, E., Annicotte, J.-S., Pradelli, L. A., Hugon, G., Matecki, S., Mornet, D., Rivier, F., and Fajas, L. (2012) E2F transcription factor-1
124. Bueno Júnior, C. R., Pantaleão, L. C., Voltarelli, V. A., Bozi, L. H. M., Brum, P. C., and Zatz, M. (2012) Combined effect of AMPK/PPAR agonists and exercise training in mdx mice functional performance. PloS ONE 7, e45699
125. Godin, R., Daussin, F., Matecki, S., Li, T., Petrof, B. J., and Burelle, Y. (2012) Peroxisome proliferator-activated receptor coactivator1-gene transfer restores mitochondrial biomass and improves mitochondrial calcium handling in post-necrotic mdx mouse skeletal muscle. J. Phsyiol. 590, 5487-5502
126. Gordon, B. S., Delgado, D. C., and Kostek, M. C. (2013) Resveratrol decreases in flammation and increases utrophin gene expression in the mdx mouse model of Duchenne muscular dystrophy. Clin. Nutr. 32, 104-111
127. Handschin, C., Kobayashi, Y. M., Chin, S., Seale, P., Campbell, K. P., and Spiegelman, B. M. (2007) PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev. 21, 770-783
128. Jahnke, V. E., Meulen Van, J. H. Der, Johnston, H. K., Ghimbovschi, S., Partridge, T., Hoffman, E. P., and Nagaraju, K. (2012) Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model. Skelet. Muscle 2, 16
129. Matsakas, A., Yadav, V., Lorca, S., and Narkar, V. (2013) Muscle ERR mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming. FASEB J. 27, 4004-4016.
130. Selsby, J. T., Morine, K. J., Pendrak, K., Barton, E. R., and Sweeney, H. L. (2012) Rescue of dystrophic skeletal muscle by PGC-1 involves a fast to slow fiber type shift in the mdx mouse. PloS ONE 7, e30063
131. Stupka, N., Plant, D. R., Schertzer, J. D., Emerson, T. M., Bassel-Duby, R., Olson, E. N., and Lynch, G. S. (2006) Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice. J. Physiol. 575.2645-656
132. Von Maltzahn, J., Renaud, J.-M., Parise, G., and Rudnicki, M. A. (2012) Wnt7a treatment ameliorates muscular dystrophy. Proc. Natl. Acad. Sci. U. S. A. 109, 20614-20619
133. Tinsley, J. M., and Davies, K. E. (1993) Utrophin: a potential replacement for dystrophin? Neuromusc. Disord. 3, 537-539
134. Karpati, G., Carpenter, S., Morris, G. E., Davies, K. E., Guerin, C., and Holland, P. (1993) Localization and quantitation of the chromosome 6-encoded dystrophin-related protein in normal and pathological human muscle. J. Neuropathol. Exp. Pathol. 52, 119-128
135. Kleopa, K. A., Drousiotou, A., Mavrikiou, E., Ormiston, A., and Kyriakides, T. (2006) Naturally occurring utrophin correlates with disease severity in Duchenne muscular dystrophy. Hum. Mol. Genet. 15, 1623-1628
136. Deconinck, A. E., Rafael, J. A., Skinner, J. A., Brown, S. C., Potter, A. C., Metzinger, L., Watt, D. J., Dickson, J. G., Tinsley, J. M., and Davies, K. E. (1997) Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell 90, 717-727
137. Rafael, J. A., Tinsley, J. M., Potter, A. C., Deconinck, A. E., and Davies, K. E. (1998) Skeletal muscle-specific expression of a utrophin transgene rescues utrophin-dystrophin deficient mice. Nat. Genet. 19, 79-82
138. Tinsley, J., Deconinck, N., Fisher, R., Kahn, D., Phelps, S., Gillis, J. M., and Davies, K. (1998) Expression of full-length utrophin prevents muscular dystrophy in mdx mice. Nat. Med. 4, 1441-1444
139. Parsons, S. A., Millay, D. P., Sargent, M. A., Naya, F. J., McNally, E. M., Sweeney, H. L., and Molkentin, J. D. (2007) Genetic disruption of calcineurin improves skeletal muscle pathology and cardiac disease in a mouse model of limb-girdle muscular dystrophy. J. Biol. Chem. 282, 10068-10078
140. Hollinger, K., Gardan-Salmon, D., Santana, C., Rice, D., Snella, E., and Selsby, J. T. (2013) Rescue of dystrophic skeletal muscle by PGC-1 involves restored expression of dystrophin-associated protein complex components and satellite cell signaling. Am. J. Physiol. 305, R13-23
141. Kotelnikova, E., Shkrob, M. A., Pyatnitskiy, M. A., Ferlini, A., and Daraselia, N. (2012) Novel approach to meta-analysis of microarray datasets reveals muscle remodeling-related drug targets and biomarkers in Duchenne muscular dystrophy. PLoS Comput. Biol. 8, e1002365
142. Guevel, L., Lavoie, J. R., Perez-Iratxeta, C., Rouger, K., Dubreil, L., Feron, M., Talon, S., Brand, M., and Megeney, L. A. (2011) Quantitative proteomic analysis of dystrophic dog muscle. J. Proteome Res. 10, 2465-2478
143. Peters, J. M., Foreman, J. E., and Gonzalez, F. J. (2011) Dissecting the role of peroxisome proliferator-activated receptor- -/- (PPAR-/-) in colon, breast, and lung carcinogenesis. Cancer Metastasis Rev. 30, 619-640
144. Pauly, M., Daussin, F., Burelle, Y., Li, T., Godin, R., Fauconnier, J., Koechlin-Ramonatxo, C., Hugon, G., Lacampagne, A., Coisy-Quivy, M., Liang, F., Hussain, S., Matecki, S., and Petrof, B. J. (2012) AMPK activation stimulates autophagy and ameliorates muscular dystrophy in the mdx mouse diaphragm. Am. J. Pathol. 181, 583-592
145. Moorwood, C., Lozynska, O., Suri, N., Napper, A. D., Diamond, S. L., and Khurana, T. S. (2011) Drug discovery for Duchenne muscular dystrophy via utrophin promoter activation screening. PloS ONE 6, e26169
146. Hori, Y. S., Kuno, A., Hosoda, R., Tanno, M., Miura, T., Shimamoto, K., and Horio, Y. (2011) Resveratrol ameliorates muscular pathology in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy. J. Pharmacol. Exp. Ther. 338, 784-794
147. Hawley, J. A., and Holloszy, J. O. (2009) Exercise: it's the real thing! Nutr. Rev. 67, 172-178
148. Hayes, A., Lynch, G., and Williams, D. (1993) The effects of endurance exercise on dystrophic mdx mice, part I: contractile and histochemical properties of intact muscles. Proc. Biol. Sci. 253, 19-25
149. Dupont-Versteegden, E. E., McCarter, R. J., and Katz, M. S. (1994) Voluntary dystrophy exercise decreases progression in diaphragm of mdx mice of muscular. J. Appl. Physiol. 77, 1736-1741
150. Hayes, A., and Williams, D. A. (1996) Beneficial effects of voluntary wheel running on the properties of dystrophic mouse muscle. J. Appl. Physiol. 80, 670-679
151. Dupont-Versteegden, E. E. (1996) Exercise and clenbuterol as strategies to decrease the progression of muscular dystrophy in mdx mice. J. Appl. Physiol. 80, 734-741
152. Hayes, A., and Williams, D. A. (1997) Contractile properties of clenbuterol-treated mdx muscle are enhanced by low-intensity swimming. J. Appl. Physiol. 82, 435-439
153. Wineinger, M. A., Abresh, R. T., Walsh, S. A., and Carter, G. T. (1998) Effects of aging and voluntary exercise on the function of dystrophic muscle from mdx mice. Am. J. Phys. Med. Rehabil. 77, 20-27
154. Hayes, A., and Williams, D. A. (1998) Contractile function and low-intensity exercise effects of old dystrophic (mdx) mice. Am. J. Physiol. 274, C1138-C1144
155. Kaczor, J. J., Hall, J. E., Payne, E., and Tarnopolsky, M. A. (2007) Low intensity training decreases markers of oxidative stress in skeletal muscle of mdx mice. Free Radic. Biol. Med. 43, 145-154
156. Call, J. A., Voelker, K. A., Wolff, A. V., Mcmillan, R. P., Evans, N. P., Hulver, M. W., Talmadge, R. J., and Grange, R. W. (2008) Endurance capacity in maturing mdx mice is markedly enhanced by combined voluntary wheel running and green tea extract. J. Appl. Physiol. 105, 923-932
157. Call, J. A., McKeehen, J. N., Novotny, S. A., and Lowe, D. A. (2010) Progressive resistance voluntary wheel running in the mdx mouse. Muscle Nerve 42, 871-880
158. Selsby, J. T., Acosta, P., Sleeper, M. M., Barton, E. R., and Sweeney, H. L. (2013) Long-term wheel running compromises diaphragm function but improves cardiac and plantarflexor function in the mdx mouse. J. Appl. Physiol. (1985) 115, 660-666
159. Vignos, P. J., Jr. and Watkins, M. P. (1966) The effect of exercise in muscular dystrophy. JAMA 197, 843-848
160. de Lateur, B. J., and Giaconi, R. M. (1979) Effect on maximal strength of submaximal exercise in Duchenne muscular dystrophy. Am. J. Phys. Med. 58, 26-36
161. Scott, O. M., Hyde, S. A., Goddard, C., Jones, R., and Dubowitz, V. (1981) Effect of exercise in Duchenne muscular dystrophy. Physiotherapy 67, 174-176
162. Vignos, P. J., Jr. (1983) Physical models of rehabilitation in neuromuscular disease. Muscle Nerve 6, 323-338
163. Ansved, T. (2001) Muscle training in muscular dystrophies. Acta Physiol. Scand. 171, 359-366
164. Eaglem, M. (2002) Report on the muscular dystrophy campaign workshop: exercise in neuromuscular diseases Newcastle, January 2002. Neuromuscul. Disord. 12, 975-983
165. Markert, C. D., Case, L. E., Carter, G. T., Furlong, P. A., and Grange, R. W. (2012) Exercise and Duchenne muscular dystrophy: where we have been and where we need to go. Muscle Nerve 45, 746-751
166. Jansen, M., de Groot, I. J., van Alfen, N., and Geurts, A. C. (2010) Physical training in boys with Duchenne muscular dystrophy: the protocol of the No Use is Disuse study. BMC Pediatr. 10, 55