Molecular Networks of Human Muscle Adaptation to Exercise and Age

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Physical activity and molecular ageing presumably interact to precipitate musculoskeletal decline in humans with age. Herein, we have delineated molecular networks for these two major components of sarcopenic risk using multiple independent clinical cohorts. We generated genome-wide transcript profiles from individuals (n = 44) who then undertook 20 weeks of supervised resistance-exercise training (RET). Expectedly, our subjects exhibited a marked range of hypertrophic responses (3% to +28%), and when applying Ingenuity Pathway Analysis (IPA) up-stream analysis to ∼580 genes that co-varied with gain in lean mass, we identified rapamycin (mTOR) signaling associating with growth (P = 1.4×10⁻³⁰). Paradoxically, those displaying most hypertrophy exhibited an inhibited mTOR activation signature, including the striking down-regulation of 70 rRNAs. Differential analysis found networks mimicking developmental processes (activated all-trans-retinoic acid (ATRA, Z-score = 4.5; P = 6×10⁻¹³) and inhibited aryl-hydrocarbon receptor signaling (AhR, Z-score = −2.3; P = 3×10⁻⁷)) with RET. Intriguingly, as ATRA and AhR gene-sets were also a feature of endurance exercise training (EET), they appear to represent “generic” physical activity responsive gene-networks. For age, we found that differential gene-expression methods do not produce consistent molecular differences between young versus old individuals. Instead, utilizing two independent cohorts (n = 45 and n = 52), with a continuum of subject ages (18–78 y), the first reproducible set of age-related transcripts in human muscle was identified. This analysis identified ∼500 genes highly enriched in post-transcriptional processes (P = 1×10⁻⁶) and with negligible links to the aforementioned generic exercise regulated gene-sets and some overlap with ribosomal genes. The RNA signatures from multiple compounds all targeting serotonin, DNA topoisomerase antagonism, and RXR activation were significantly related to the muscle age-related genes. Finally, a number of specific chromosomal loci, including 1q12 and 13q21, contributed by more than chance to the age-related gene list (P = 0.01–0.005), implying possible epigenetic events. We conclude that human muscle age-related molecular processes appear distinct from the processes regulated by those of physical activity.

Vyšlo v časopise: Molecular Networks of Human Muscle Adaptation to Exercise and Age. PLoS Genet 9(3): e32767. doi:10.1371/journal.pgen.1003389
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003389

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Zdroje

1. AthertonPJ, SmithK (2012) Muscle protein synthesis in response to nutrition and exercise. The Journal of physiology 590 : 1049–1057.

2. BouchardC, RankinenT, TimmonsJA (2011) Genomics and Genetics in the Biology of Adaptation to Exercise. Comprehensive Physiology 1603–1648.

3. StephensNA, GallagherIJ, RooyackersO, SkipworthRJ, TanBH, et al. (2010) Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia. Genome Med 2 : 1.

4. GallagherIJ, StephensNA, MacDonaldAJ, SkipworthRJE, HusiH, et al. (2012) Suppression of skeletal muscle turnover in cancer cachexia: evidence from the transcriptome in sequential human muscle biopsies. Clinical cancer research: an official journal of the American Association for Cancer Research 18 : 2817–2827.

5. GloverEI, PhillipsSM, OatesBR, TangJE, TarnopolskyMA, et al. (2008) Immobilization induces anabolic resistance in human myofibrillar protein synthesis with low and high dose amino acid infusion. The Journal of physiology 586 : 6049–6061.

6. GustafssonT, OsterlundT, FlanaganJN, Von WaldénF, TrappeTA, et al. (2010) Effects of 3 days unloading on molecular regulators of muscle size in humans. Journal of applied physiology (Bethesda, Md: 1985) 109 : 721–727.

7. KumarV, SelbyA, RankinD, PatelR, AthertonP, et al. (2009) Age-related differences in the dose-response relationship of muscle protein synthesis to resistance exercise in young and old men. The Journal of physiology 587 : 211–217.

8. MitchellCJ, Churchward-VenneTA, WestDWD, BurdNA, BreenL, et al. (2012) Resistance exercise load does not determine training-mediated hypertrophic gains in young men. Journal of applied physiology (Bethesda, Md: 1985) 113 : 71–77.

9. Churchward-VenneTA, BurdNA, PhillipsSM (2012) Research Group EM (2012) Nutritional regulation of muscle protein synthesis with resistance exercise: strategies to enhance anabolism. Nutrition & metabolism 9 : 40.

10. RommelC, BodineSC, ClarkeBA, RossmanR, NunezL, et al. (2001) Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nature cell biology 3 : 1009–1013.

11. IadevaiaV, HuoY, ZhangZ, FosterLJ, ProudCG (2012) Roles of the mammalian target of rapamycin, mTOR, in controlling ribosome biogenesis and protein synthesis. Biochemical Society transactions 40 : 168–172.

12. TerzisG, GeorgiadisG, StratakosG, VogiatzisI, KavourasS, et al. (2008) Resistance exercise-induced increase in muscle mass correlates with p70S6 kinase phosphorylation in human subjects. Eur J Appl Physiol 102 : 145–152.

13. DrummondMJ, MiyazakiM, DreyerHC, PenningsB, DhananiS, et al. (2009) Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis. Journal of applied physiology (Bethesda, Md: 1985) 106 : 1403–1411.

14. DickinsonJM, FryCS, DrummondMJ, GundermannDM, WalkerDK, et al. (n.d.) Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids. J Nutr 141 : 856–862.

15. FryCS, DrummondMJ, GlynnEL, DickinsonJM, GundermannDM, et al. (2011) Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis. Skeletal muscle 1 : 11.

16. LiM, VerdijkLB, SakamotoK, ElyB, Van LoonLJC, et al. (2012) Reduced AMPK-ACC and mTOR signaling in muscle from older men, and effect of resistance exercise. Mechanisms of ageing and development 133 : 655–664.

17. FarnfieldMM, BreenL, CareyKA, GarnhamA, Cameron-SmithD (2012) Activation of mTOR signalling in young and old human skeletal muscle in response to combined resistance exercise and whey protein ingestion. Applied physiology, nutrition, and metabolism = Physiologie appliquée, nutrition et métabolisme 37 : 21–30.

18. WestDWD, KujbidaGW, MooreDR, AthertonP, BurdNA, et al. (2009) Resistance exercise-induced increases in putative anabolic hormones do not enhance muscle protein synthesis or intracellular signalling in young men. J Physiol 587 : 5239–5247.

19. SpangenburgEE, Le RoithD, WardCW, BodineSC (2008) A functional insulin-like growth factor receptor is not necessary for load-induced skeletal muscle hypertrophy. The Journal of physiology 586 : 283–291.

20. GoodmanCA, FreyJW, MabreyDM, JacobsBL, LincolnHC, et al. (2011) The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth. The Journal of physiology 589 : 5485–5501.

21. CameraDM, EdgeJ, ShortMJ, HawleyJA, CoffeyVG (2010) Early time course of Akt phosphorylation after endurance and resistance exercise. Medicine and science in sports and exercise 42 : 1843–1852.

22. TimmonsJA (2011) Variability in training-induced skeletal muscle adaptation. J Appl Physiol 110 : 846–853.

23. MelovS, TarnopolskyMA, BeckmanK, FelkeyK, HubbardA (2007) Resistance exercise reverses aging in human skeletal muscle. PLoS ONE 2: e465 doi:10.1371/journal.pone.0000465.

24. RaueU, TrappeTA, EstremST, QianH-R, HelveringLM, et al. (2012) Transcriptome signature of resistance exercise adaptations: mixed muscle and fiber type specific profiles in young and old adults. Journal of applied physiology (Bethesda, Md: 1985) 112 : 1625–1636.

25. BellR, HubbardA, ChettierR, ChenD, MillerJP, et al. (2009) A human protein interaction network shows conservation of aging processes between human and invertebrate species. PLoS Genet 5: e1000414 doi:10.1371/journal.pgen.1000414.

26. WelleS, BrooksAI, DelehantyJM, NeedlerN, BhattK, et al. (2004) Skeletal muscle gene expression profiles in 20–29 year old and 65–71 year old women. Exp Gerontol 39 : 369–377.

27. GiresiPG, StevensonEJ, TheilhaberJ, KoncarevicA, ParkingtonJ, et al. (2005) Identification of a molecular signature of sarcopenia. Physiol Genomics 21 : 253–263.

28. DavidsenPK, GallagherIJ, HartmanJW, TarnopolskyMA, DelaF, et al. (2011) High responders to resistance exercise training demonstrate differential regulation of skeletal muscle microRNA expression. J Appl Physiol 110 : 309–317.

29. KellerP, VollaardNB, GustafssonT, GallagherIJ, SundbergCJ, et al. (2011) A transcriptional map of the impact of endurance exercise training on skeletal muscle phenotype. J Appl Physiol 110 : 46–59.

30. BouleNG, WeisnagelSJ, LakkaTA, TremblayA, BergmanRN, et al. (2005) Effects of exercise training on glucose homeostasis: the HERITAGE Family Study. Diabetes Care 28 : 108–114.

31. TimmonsJa, JanssonE, FischerH, GustafssonT, GreenhaffPL, et al. (2005) Modulation of extracellular matrix genes reflects the magnitude of physiological adaptation to aerobic exercise training in humans. BMC biology 3 : 19. A.

32. VollaardNB, Constantin-TeodosiuD, FredrikssonK, RooyackersO, JanssonE, et al. (2009) Systematic analysis of adaptations in aerobic capacity and submaximal energy metabolism provides a unique insight into determinants of human aerobic performance. J Appl Physiol 106 : 1479–1486.

33. KellerP, VollaardN, BabrajJ, BallD, SewellDA, et al. (2007) Using systems biology to define the essential biological networks responsible for adaptation to endurance exercise training. Biochem Soc Trans 35 : 1306–1309.

34. TimmonsJA, KnudsenS, RankinenT, KochLG, SarzynskiM, et al. (2010) Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans. Journal of applied physiology 108 : 1487–1496.

35. FELCIANORM, BAVARIS, RICHARDSDR, BILLAUDJ-N, WARRENT, et al. (2013) Predictive systems biology approach to broad-spectrum, host-directed drug target discovery in infectious diseases. Pacific Symposium on Biocomputing 18 : 17–28 Available: http://psb.stanford.edu/psb-online/proceedings/psb13/felciano.pdf

36. TusherVG, TibshiraniR, ChuG (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98 : 5116–5121.

37. AthertonPJ, BabrajJ, SmithK, SinghJ, RennieMJ, et al. (2005) Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation. Faseb J 19 : 786–788.

38. GustafsonWC, WeissWA (2010) Myc proteins as therapeutic targets. Oncogene 29 : 1249–1259.

39. WelleS, BrooksAI, DelehantyJM, NeedlerN, ThorntonCA (2003) Gene expression profile of aging in human muscle. Physiol Genomics 14 : 149–159.

40. GallagherI (2010) Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in Type 2 Diabetes. Genome Med 2 : 9.

41. TimmonsJA, NorrbomJ, ScheeleC, ThonbergH, WahlestedtC, et al. (2006) Expression profiling following local muscle inactivity in humans provides new perspective on diabetes-related genes. Genomics 87 : 165–172.

42. BouchardC, LeonAS, RaoDC, SkinnerJS, WilmoreJH, et al. (1995) The HERITAGE family study. Aims, design, and measurement protocol. Med Sci Sports Exerc 27 : 721–729.

43. De PreterK, BarriotR, SpelemanF, VandesompeleJ, MoreauY (2008) Positional gene enrichment analysis of gene sets for high-resolution identification of overrepresented chromosomal regions. Nucleic acids research 36: e43.

44. TimmonsJA, BaarK, DavidsenPK, AthertonPJ (2012) Is irisin a human exercise gene? Nature 488: E9–E10.

45. KadiF, PonsotE (2010) The biology of satellite cells and telomeres in human skeletal muscle: effects of aging and physical activity. Scandinavian journal of medicine & science in sports 20 : 39–48.

46. McCallGE, ByrnesWC, DickinsonA, PattanyPM, FleckSJ (1996) Muscle fiber hypertrophy, hyperplasia, and capillary density in college men after resistance training. Journal of applied physiology (Bethesda, Md: 1985) 81 : 2004–2012.

47. HolmL, Van HallG, RoseAJ, MillerBF, DoessingS, et al. (2010) Contraction intensity and feeding affect collagen and myofibrillar protein synthesis rates differently in human skeletal muscle. American journal of physiology Endocrinology and metabolism 298: E257–69.

48. HalevyO, LermanO (1993) Retinoic acid induces adult muscle cell differentiation mediated by the retinoic acid receptor-alpha. Journal of cellular physiology 154 : 566–572.

49. BunaciuRP, YenA (2011) Activation of the aryl hydrocarbon receptor AhR Promotes retinoic acid-induced differentiation of myeloblastic leukemia cells by restricting expression of the stem cell transcription factor Oct4. Cancer research 71 : 2371–2380.

50. McKayBR, O'ReillyCE, PhillipsSM, TarnopolskyMA, PariseG (2008) Co-expression of IGF-1 family members with myogenic regulatory factors following acute damaging muscle-lengthening contractions in humans. The Journal of physiology 586 : 5549–5560.

51. PariseG, McKinnellIW, RudnickiMA (2008) Muscle satellite cell and atypical myogenic progenitor response following exercise. Muscle & nerve 37 : 611–619 Available: http://www.ncbi.nlm.nih.gov/pubmed/18351585 Accessed 12 October 2012.

52. GeY, SunY, ChenJ (2011) IGF-II is regulated by microRNA-125b in skeletal myogenesis. The Journal of cell biology 192 : 69–81.

53. SaitoA, SugawaraA, UrunoA, KudoM, KagechikaH, et al. (2007) All-trans retinoic acid induces in vitro angiogenesis via retinoic acid receptor: possible involvement of paracrine effects of endogenous vascular endothelial growth factor signaling. Endocrinology 148 : 1412–1423.

54. JohnstonAPW, BakerJ, BellamyLM, McKayBR, De LisioM, et al. (2010) Regulation of muscle satellite cell activation and chemotaxis by angiotensin II. PLoS ONE 5: e15212 doi:10.1371/journal.pone.0015212.

55. GorskiDH, WalshK (2000) The Role of Homeobox Genes in Vascular Remodeling and Angiogenesis. Circulation Research 87 : 865–872.

56. PhillipsB, WilliamsJ, AthertonPJ, SmithK, HildebrandtW, et al. (2011) Resistance exercise training improves age-related declines in leg vascular conductance and rejuvenates acute leg blood flow responses to feeding and exercise. Journal of applied physiology (Bethesda, Md: 1985) 112 : 347–353.

57. GustafssonT, PuntschartA, KaijserL, JanssonE, SundbergCJ (1999) Exercise-induced expression of angiogenesis-related transcription and growth factors in human skeletal muscle. Am J Physiol 276: H679–85.

58. AxelD (2001) All-trans retinoic acid regulates proliferation, migration, differentiation, and extracellular matrix turnover of human arterial smooth muscle cells. Cardiovascular Research 49 : 851–862.

59. OhtakeF, BabaA, TakadaI, OkadaM, IwasakiK, et al. (2007) Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 446 : 562–566.

60. AbdelrahimM, SmithR, SafeS (2003) Aryl hydrocarbon receptor gene silencing with small inhibitory RNA differentially modulates Ah-responsiveness in MCF-7 and HepG2 cancer cells. Molecular pharmacology 63 : 1373–1381.

61. AmelnH, GustafssonT, SundbergCJ, OkamotoK, JanssonE, et al. (2005) Physiological activation of hypoxia inducible factor-1 in human skeletal muscle. Faseb J 19 : 1009–1011.

62. AndreasenEA, MathewLK, LöhrCV, HassonR, TanguayRL (2007) Aryl hydrocarbon receptor activation impairs extracellular matrix remodeling during zebra fish fin regeneration. Toxicological sciences: an official journal of the Society of Toxicology 95 : 215–226.

63. MurphyKA, QuadroL, WhiteLA (2007) The intersection between the aryl hydrocarbon receptor (AhR) -⁠ and retinoic acid-signaling pathways. Vitamins and hormones 75 : 33–67.

64. BammanMM, PetrellaJK, KimJS, MayhewDL, CrossJM (2007) Cluster analysis tests the importance of myogenic gene expression during myofiber hypertrophy in humans. J Appl Physiol 102 : 2232–2239.

65. MooreDR, Del BelNC, NiziKI, HartmanJW, TangJE, et al. (2007) Resistance training reduces fasted -⁠ and fed-state leucine turnover and increases dietary nitrogen retention in previously untrained young men. J Nutr 137 : 985–991.

66. Von WaldenF, CasagrandeV, Östlund FarrantsA-K, NaderGA (2012) Mechanical loading induces the expression of a Pol I regulon at the onset of skeletal muscle hypertrophy. American journal of physiology Cell physiology 302: C1523–30.

67. WestDWD, BurdNA, CoffeyVG, BakerSK, BurkeLM, et al. (2011) Rapid aminoacidemia enhances myofibrillar protein synthesis and anabolic intramuscular signaling responses after resistance exercise. The American journal of clinical nutrition 94 : 795–803 doi:10.3945/ajcn.111.013722.

68. MooreDR, AthertonPJ, RennieMJ, TarnopolskyMA, PhillipsSM (2011) Resistance exercise enhances mTOR and MAPK signalling in human muscle over that seen at rest after bolus protein ingestion. Acta physiologica (Oxford, England) 201 : 365–372.

69. AthertonPJ, EtheridgeT, WattPW, WilkinsonD, SelbyA, et al. (2010) Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. The American journal of clinical nutrition 92 : 1080–1088.

70. GreenhaffPL, KaragounisLG, PeirceN, SimpsonEJ, HazellM, et al. (2008) Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle. Am J Physiol Endocrinol Metab 295: E595–604.

71. MayhewDL, KimJS, CrossJM, FerrandoAA, BammanMM (2009) Translational signaling responses preceding resistance training-mediated myofiber hypertrophy in young and old humans. J Appl Physiol 107 : 1655–1662.

72. KenyonCJ (2010) The genetics of ageing. Nature 464 : 504–512.

73. JanssenI, HeymsfieldSB, RossR (2002) Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc 50 : 889–896.

74. GoodmanCA, MiuMH, FreyJW, MabreyDM, LincolnHC, et al. (2011) A phosphatidylinositol 3-kinase/protein kinase B-independent activation of mammalian target of rapamycin signaling is sufficient to induce skeletal muscle hypertrophy. Mol Biol Cell 21 : 3258–3268.

75. BaarK, EsserK (1999) Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. Am J Physiol 276: C120–7.

76. MahoneyDJ, PariseG, MelovS, SafdarA, TarnopolskyMA (2005) Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exercise. Faseb J 19 : 1498–1500.

77. ZhengJ-Y, YuD, ForooharM, KoE, ChanJ, et al. (2003) Regulation of the expression of the prostate-specific antigen by claudin-7. The Journal of membrane biology 194 : 187–197.

78. KimHW, HaSH, LeeMN, HustonE, KimD-H, et al. (2010) Cyclic AMP controls mTOR through regulation of the dynamic interaction between Rheb and phosphodiesterase 4D. Molecular and cellular biology 30 : 5406–5420.

79. DedeicZ, CeteraM, CohenTV, HolaskaJM (2011) Emerin inhibits Lmo7 binding to the Pax3 and MyoD promoters and expression of myoblast proliferation genes. Journal of cell science 124 : 1691–1702.

80. LipinskiC, HopkinsA (2004) Navigating chemical space for biology and medicine. Nature 432 : 855–861.

81. ShanksN, GreekR, GreekJ (2009) Are animal models predictive for humans? Philosophy, ethics, and humanities in medicine: PEHM 4 : 2.

82. HopkinsAL (2008) Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 4 : 682–690.

83. FredrikssonK, TjäderI, KellerP, PetrovicN, AhlmanB, et al. (2008) Dysregulation of mitochondrial dynamics and the muscle transcriptome in ICU patients suffering from sepsis induced multiple organ failure. PLoS ONE 3: e3686 doi:10.1371/journal.pone.0003686.

84. TimmonsJa (2011) What happens if you pose the wrong questions? The Journal of physiology 589 : 4799–4801.

85. GallagherD, VisserM, De MeersmanRE, SepulvedaD, BaumgartnerRN, et al. (1997) Appendicular skeletal muscle mass: effects of age, gender, and ethnicity. J Appl Physiol 83 : 229–239.

86. LambJ, CrawfordED, PeckD, ModellJW, BlatIC, et al. (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313 : 1929–1935.