Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy


Skeletal muscle has a central role in body posture, mobility and whole-body metabolism. SIRT1 is an enzyme expressed in skeletal muscle, as well as in most mammalian tissues, and has been shown to sense metabolic cues from the environment and mediate changes in these tissues, counteracting age and metabolic diseases. Here we generated and studied mice that express high levels of SIRT1 in skeletal muscle. We found that increased levels of SIRT1 in skeletal muscle led to gene expression changes similar to those that normally occur with endurance exercise. We also observed that SIRT1 overexpression counteracts muscle atrophy, a hallmark of aging muscle, and the muscle degenerative disease Duchenne muscular dystrophy (DMD). DMD is a debilitating disease caused by a mutation in the structural protein dystrophin. SIRT1 overexpression ameliorated the pathophysiology of DMD disease in a mouse model. Our results offer the hope that drugs that constitutively activate the enzymatic activity of SIRT1 might be used to cure muscle degenerative diseases.


Vyšlo v časopise: Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004490
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004490

Souhrn

Skeletal muscle has a central role in body posture, mobility and whole-body metabolism. SIRT1 is an enzyme expressed in skeletal muscle, as well as in most mammalian tissues, and has been shown to sense metabolic cues from the environment and mediate changes in these tissues, counteracting age and metabolic diseases. Here we generated and studied mice that express high levels of SIRT1 in skeletal muscle. We found that increased levels of SIRT1 in skeletal muscle led to gene expression changes similar to those that normally occur with endurance exercise. We also observed that SIRT1 overexpression counteracts muscle atrophy, a hallmark of aging muscle, and the muscle degenerative disease Duchenne muscular dystrophy (DMD). DMD is a debilitating disease caused by a mutation in the structural protein dystrophin. SIRT1 overexpression ameliorated the pathophysiology of DMD disease in a mouse model. Our results offer the hope that drugs that constitutively activate the enzymatic activity of SIRT1 might be used to cure muscle degenerative diseases.


Zdroje

1. Bassel-DubyR, OlsonEN (2006) Signaling pathways in skeletal muscle remodeling. Annu Rev Biochem 75: 19–37.

2. BoothFW, ThomasonDB (1991) Molecular and cellular adaptation of muscle in response to exercise: perspectives of various models. Physiol Rev 71: 541–585.

3. PetteD, StaronRS (2001) Transitions of muscle fiber phenotypic profiles. Histochem Cell Biol 115: 359–372.

4. BerchtoldMW, BrinkmeierH, MuntenerM (2000) Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. Physiol Rev 80: 1215–1265.

5. OlsonEN, WilliamsRS (2000) Remodeling muscles with calcineurin. Bioessays 22: 510–519.

6. AspnesLE, LeeCM, WeindruchR, ChungSS, RoeckerEB, et al. (1997) Caloric restriction reduces fiber loss and mitochondrial abnormalities in aged rat muscle. Faseb J 11: 573–581.

7. CivitareseAE, CarlingS, HeilbronnLK, HulverMH, UkropcovaB, et al. (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 4: e76.

8. ChalkiadakiA, GuarenteL (2012) Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat Rev Endocrinol 8: 287–296.

9. ChalkiadakiA, GuarenteL (2012) High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction. Cell Metab 16: 180–188.

10. CantoC, Gerhart-HinesZ, FeigeJN, LagougeM, NoriegaL, et al. (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458: 1056–1060.

11. CantoC, JiangLQ, DeshmukhAS, MatakiC, CosteA, et al. (2010) Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11: 213–219.

12. Gerhart-HinesZ, RodgersJT, BareO, LerinC, KimSH, et al. (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. Embo J 26: 1913–1923.

13. WuZ, PuigserverP, AnderssonU, ZhangC, AdelmantG, et al. (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98: 115–124.

14. LinJ, WuH, TarrPT, ZhangCY, WuZ, et al. (2002) Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418: 797–801.

15. SandriM, LinJ, HandschinC, YangW, AranyZP, et al. (2006) PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A 103: 16260–16265.

16. WenzT, RossiSG, RotundoRL, SpiegelmanBM, MoraesCT (2009) Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A 106: 20405–20410.

17. ChoiCS, BefroyDE, CodellaR, KimS, ReznickRM, et al. (2008) Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc Natl Acad Sci U S A 105: 19926–19931.

18. GomesAP, PriceNL, LingAJ, MoslehiJJ, MontgomeryMK, et al. (2013) Declining NAD(+) Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell 155: 1624–1638.

19. HandschinC, KobayashiYM, ChinS, SealeP, CampbellKP, et al. (2007) PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev 21: 770–783.

20. BogdanovichS, PerkinsKJ, KragTO, KhuranaTS (2004) Therapeutics for Duchenne muscular dystrophy: current approaches and future directions. J Mol Med 82: 102–115.

21. WebsterC, SilbersteinL, HaysAP, BlauHM (1988) Fast muscle fibers are preferentially affected in Duchenne muscular dystrophy. Cell 52: 503–513.

22. Ibraghimov-BeskrovnayaO, ErvastiJM, LeveilleCJ, SlaughterCA, SernettSW, et al. (1992) Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature 355: 696–702.

23. ByersTJ, KunkelLM, WatkinsSC (1991) The subcellular distribution of dystrophin in mouse skeletal, cardiac, and smooth muscle. J Cell Biol 115: 411–421.

24. SealockR, ButlerMH, KramarcyNR, GaoKX, MurnaneAA, et al. (1991) Localization of dystrophin relative to acetylcholine receptor domains in electric tissue and adult and cultured skeletal muscle. J Cell Biol 113: 1133–1144.

25. LoveDR, HillDF, DicksonG, SpurrNK, BythBC, et al. (1989) An autosomal transcript in skeletal muscle with homology to dystrophin. Nature 339: 55–58.

26. MiuraP, JasminBJ (2006) Utrophin upregulation for treating Duchenne or Becker muscular dystrophy: how close are we? Trends Mol Med 12: 122–129.

27. TinsleyJ, DeconinckN, FisherR, KahnD, PhelpsS, et al. (1998) Expression of full-length utrophin prevents muscular dystrophy in mdx mice. Nat Med 4: 1441–1444.

28. TinsleyJM, PotterAC, PhelpsSR, FisherR, TrickettJI, et al. (1996) Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene. Nature 384: 349–353.

29. SelsbyJT, MorineKJ, PendrakK, BartonER, SweeneyHL (2012) Rescue of dystrophic skeletal muscle by PGC-1alpha involves a fast to slow fiber type shift in the mdx mouse. PLoS One 7: e30063.

30. JohnsonJE, WoldBJ, HauschkaSD (1989) Muscle creatine kinase sequence elements regulating skeletal and cardiac muscle expression in transgenic mice. Mol Cell Biol 9: 3393–3399.

31. GomesMD, LeckerSH, JagoeRT, NavonA, GoldbergAL (2001) Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A 98: 14440–14445.

32. LeckerSH, JagoeRT, GilbertA, GomesM, BaracosV, et al. (2004) Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. Faseb J 18: 39–51.

33. SandriM, SandriC, GilbertA, SkurkC, CalabriaE, et al. (2004) Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117: 399–412.

34. StittTN, DrujanD, ClarkeBA, PanaroF, TimofeyvaY, et al. (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.

35. ChenD, BrunoJ, EaslonE, LinSJ, ChengHL, et al. (2008) Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev 22: 1753–1757.

36. SchiaffinoS, ReggianiC (1994) Myosin isoforms in mammalian skeletal muscle. J Appl Physiol 77: 493–501.

37. RodgersJT, LerinC, HaasW, GygiSP, SpiegelmanBM, et al. (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434: 113–118.

38. HondaresE, Pineda-TorraI, IglesiasR, StaelsB, VillarroyaF, et al. (2007) PPARdelta, but not PPARalpha, activates PGC-1alpha gene transcription in muscle. Biochem Biophys Res Commun 354: 1021–1027.

39. PriceNL, GomesAP, LingAJ, DuarteFV, Martin-MontalvoA, et al. (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15: 675–690.

40. LaplanteM, SabatiniDM (2012) mTOR signaling in growth control and disease. Cell 149: 274–293.

41. BruningJC, MichaelMD, WinnayJN, HayashiT, HorschD, et al. (1998) A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 2: 559–569.

42. ChengHL, MostoslavskyR, SaitoS, ManisJP, GuY, et al. (2003) Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A 100: 10794–10799.

43. MenziesKJ, SinghK, SaleemA, HoodDA (2013) Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J Biol Chem 288: 6968–6979.

44. PhilpA, ChenA, LanD, MeyerGA, MurphyAN, et al. (2011) Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise. J Biol Chem 286: 30561–30570.

45. BulfieldG, SillerWG, WightPA, MooreKJ (1984) X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci U S A 81: 1189–1192.

46. GhediniPC, VielTA, HondaL, AvellarMC, GodinhoRO, et al. (2008) Increased expression of acetylcholine receptors in the diaphragm muscle of MDX mice. Muscle Nerve 38: 1585–1594.

47. BrusseeV, TardifF, TremblayJP (1997) Muscle fibers of mdx mice are more vulnerable to exercise than those of normal mice. Neuromuscul Disord 7: 487–492.

48. SchenkS, McCurdyCE, PhilpA, ChenMZ, HollidayMJ, et al. (2011) Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. J Clin Invest 121: 4281–4288.

49. GuarenteL (2011) Sirtuins, aging, and metabolism. Cold Spring Harb Symp Quant Biol 76: 81–90.

50. AranyZ, HeH, LinJ, HoyerK, HandschinC, et al. (2005) Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 1: 259–271.

51. HandschinC, ChinS, LiP, LiuF, Maratos-FlierE, et al. (2007) Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J Biol Chem 282: 30014–30021.

52. GengT, LiP, OkutsuM, YinX, KwekJ, et al. (2010) PGC-1alpha plays a functional role in exercise-induced mitochondrial biogenesis and angiogenesis but not fiber-type transformation in mouse skeletal muscle. Am J Physiol Cell Physiol 298: C572–579.

53. RoweGC, El-KhouryR, PattenIS, RustinP, AranyZ (2012) PGC-1alpha is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle. PLoS One 7: e41817.

54. CohenHY, MillerC, BittermanKJ, WallNR, HekkingB, et al. (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305: 390–392.

55. HubbardBP, GomesAP, DaiH, LiJ, CaseAW, et al. (2013) Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339: 1216–1219.

56. HowitzKT, BittermanKJ, CohenHY, LammingDW, LavuS, et al. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425: 191–196.

57. HoriYS, KunoA, HosodaR, TannoM, MiuraT, et al. (2011) Resveratrol ameliorates muscular pathology in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy. J Pharmacol Exp Ther 338: 784–794.

58. GoodyMF, KellyMW, ReynoldsCJ, KhalilA, CrawfordBD, et al. (2012) NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy. PLoS Biol 10: e1001409.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 7
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa