Biotechnology and Bioprocess Engineering

, Volume 19, Issue 5, pp 811–828 | Cite as

Gender-dimorphic regulation of muscular proteins in response to high fat diet and sex steroid hormones

  • Kanikkai Raja Aseer
  • Sang Woo Kim
  • Dong Gun Lee
  • Jong Won Yun
Research Paper


To investigate the roles of gender-dependent obesity, we investigated the effects of high fat diet (HFD) and sex steroid hormones on the fiber-type dependent expression of contractile and metabolic regulatory pathway proteins in gastrocnemius (G) and soleus (S) muscle tissue of male and female rats. The results revealed that estrogen (E2) negatively influences body weight gain, whereas testosterone (DHT) has positive effects. Additionally, E2 appeared to play an essential role in initiating muscle contraction and mediating glucose and lipid metabolism events via AMPK and AKT pathways. The elevated expression of ERα contributed to the expression of muscular proteins in a fiber-type and gender-dependent manner. E2 treatment increased the protein levels of AMPK, thereby activating downstream lipid metabolic proteins such as PPARγ, ACSL1, LPL, and A-FABP. Such cooperatively activating proteins enhanced fatty acid oxidation, attenuating TG accumulation. E2 stimulated AKT and AMPK activation suggests that these proteins enhanced GLUT4 expression. More importantly, the S muscle of HFD-fed control females showed higher expressions of MYH, TPM1α, and TnI, while only MYH and TnI were upregulated in males treated with E2, indicating that females may be more resistant to HFD-increased metabolic complications. Similarly, E2 treatment enhanced metabolic regulatory proteins in males, indicating that they are more susceptible to metabolic dysregulation than females. To the best our knowledge, this is the first report to distinguish the fatty acid uptake and oxidation between two types of muscle in both genders.


obesity sex hormone gender dimorphism lipid oxidation muscle contraction 


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  1. 1.
    Wild, S., G. Roglic, A. Green, R. Sicree, and H. King (2004) Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabet. Care. 27: 1047–1053.CrossRefGoogle Scholar
  2. 2.
    Alberti, K. G., P. Zimmet, and J. Shaw (2006) Metabolic syndrome-a new world-wide definition. A consensus statement from the international diabetes federation. Diabet. Med. 23: 469–480.CrossRefGoogle Scholar
  3. 3.
    Hill, J. W., J. K. Elmquist, and C. F. Elias (2008) Hypothalamic pathways linking energy balance and reproduction. Am. J. Physiol. Endocrinol. Metab. 294: 827–832.CrossRefGoogle Scholar
  4. 4.
    Shi, H., R. J. Seeley, and D. J. Clegg (2009) Sexual differences in the control of energy homeostasis. Front. Neuroendocrinol. 30: 396–404.CrossRefGoogle Scholar
  5. 5.
    Mauvais-Jarvis, F. (2011) Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol. Metab. 22: 24–33.CrossRefGoogle Scholar
  6. 6.
    Carr, M. C. (2003) The emergence of the metabolic syndrome with menopause. J. Clin. Endocrinol. Metab. 88: 2404–2411.CrossRefGoogle Scholar
  7. 7.
    Zitzmann, M. (2009) Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat. Rev. Endocrinol. 5: 673–681.CrossRefGoogle Scholar
  8. 8.
    Maltin, C. A. (2008) Muscle development and obesity: Is there a relationship? Organogen. 4: 158–169.CrossRefGoogle Scholar
  9. 9.
    Simoneau, J. A. and C. Bouchard (1989) Human variation in skeletal muscle fiber-type proportion and enzyme activities. Am. J. Physiol. 257: 567–572.Google Scholar
  10. 10.
    Roth, S. M., R. E. Ferrell, D. G. Peters, E. J. Metter, B. F. Hurley, and M. A. Rogers (2002) Influence of age, sex, and strength training on human muscle gene expression determined by microarray. Physiol. Genomics. 10: 181–190.Google Scholar
  11. 11.
    Maher, A. C., M. Akhtar, J. Vockley, and M. A. Tarnopolsky (2010) Women have higher protein content of beta-oxidation enzymes in skeletal muscle than men. PLoS One. 5: e12025.CrossRefGoogle Scholar
  12. 12.
    Booth, F. W. and D. B. Thomason (1991) Molecular and cellular adaptation of muscle in response to exercise: Perspectives of various models. Physiol. Rev. 71: 541–585.Google Scholar
  13. 13.
    Berchtold, M. W., H. Brinkmeier, and M. Muntener (2000) Calcium ion in skeletal muscle: Its crucial role for muscle function, plasticity, and disease. Physiol. Rev. 80: 1215–1265.Google Scholar
  14. 14.
    Olson, E. N. and R. S. Williams (2000) Remodeling muscles with calcineurin. Bioessays. 22: 510–519.CrossRefGoogle Scholar
  15. 15.
    Abou Mrad, J., F. Yakubu, D. Lin, J. C. Peters, J. B. Atkinson, and J. O. Hill (1992) Skeletal muscle composition in dietary obesity-susceptible and dietary obesity-resistant rats. Am. J. Physiol. 262: 684–688.Google Scholar
  16. 16.
    Leney, S. E. and J. M. Tavare (2009) The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets. J. Endocrinol. 203: 1–18.CrossRefGoogle Scholar
  17. 17.
    Santos, J. M., S. B. Ribeiro, A. R. Gaya, H. J. Appell, and J. A. Duarte (2008) Skeletal muscle pathways of contraction-enhanced glucose uptake. Int. J. Sports Med. 29: 785–794.CrossRefGoogle Scholar
  18. 18.
    Douen, A. G., T. Ramlal, S. Rastogi, P. J. Bilan, G. D. Cartee, M. Vranic, J. O. Holloszy, and A. Klip (1990) Exercise induces recruitment of the “insulin-responsive glucose transporter”. Evidence for distinct intracellular insulin- and exercise-recruitable transporter pools in skeletal muscle. J. Biol. Chem. 265: 13427–13430.Google Scholar
  19. 19.
    Dolan, P. L., E. B. Tapscott, P. J. Dorton, and G. L. Dohm (1993) Contractile activity restores insulin responsiveness in skeletal muscle of obese Zucker rats. Biochem. J. 289: 423–426.Google Scholar
  20. 20.
    McCormick, K. M., K. L. Burns, C. M. Piccone, L. E. Gosselin, and G. A. Brazeau (2004) Effects of ovariectomy and estrogen on skeletal muscle function in growing rats. J. Muscle Res. Cell. Motil. 25: 21–27.CrossRefGoogle Scholar
  21. 21.
    Yoshioka, M., A. Boivin, C. Bolduc, and J. St-Amand (2007) Gender difference of androgen actions on skeletal muscle transcriptome. J. Mol. Endocrinol. 39: 119–133.CrossRefGoogle Scholar
  22. 22.
    Ploug, T., H. Galbo, J. Vinten, M. Jorgensen, and E. A. Richter (1987) Kinetics of glucose transport in rat muscle: effects of insulin and contractions. Am. J. Physiol. 253: 12–20.Google Scholar
  23. 23.
    Eskes, T. and C. Haanen (2007) Why do women live longer than men? Eur. J. Obstet. Gynecol. Reprod. Biol. 133: 126–133.CrossRefGoogle Scholar
  24. 24.
    Narkar, V. A., M. Downes, R. T. Yu, E. Embler, Y. X. Wang, E. Banayo, M. M. Mihaylova, M. C. Nelson, Y. Zou, H. Juguilon, H. Kang, R. J. Shaw, and R. M. Evans (2008) AMPK and PPAR-delta agonists are exercise mimetics. Cell. 134: 405–415.CrossRefGoogle Scholar
  25. 25.
    Bradford, M. M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248–254.CrossRefGoogle Scholar
  26. 26.
    Green, H. J., I. G. Fraser, and D. A. Ranney (1984) Male and female differences in enzyme activities of energy metabolism in vastus lateralis muscle. J. Neurol. Sci. 65: 323–331.CrossRefGoogle Scholar
  27. 27.
    Komi, P. V. and J. Karlsson (1978) Skeletal muscle fibre types, enzyme activities and physical performance in young males and females. Acta. Physiol. Scand. 103: 210–218.CrossRefGoogle Scholar
  28. 28.
    Mauvais-Jarvis, F., D. J. Clegg, and A. L. Hevener (2013) The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34: 309–338.CrossRefGoogle Scholar
  29. 29.
    Heikkinen, J., E. Kyllonen, E. Kurttila-Matero, G. Wilen-Rosenqvist, K. S. Lankinen, H. Rita, and H. K. Vaananen (1997) HRT and exercise: effects on bone density, muscle strength and lipid metabolism. A placebo controlled 2-year prospective trial on two estrogen-progestin regimens in healthy postmenopausal women. Maturitas. 26: 139–149.CrossRefGoogle Scholar
  30. 30.
    Gayan-Ramirez, G., M. van de Casteele, H. Rollier, J. Fevery, F. Vanderhoydonc, G. Verhoeven, and M. Decramer (1998) Biliary cirrhosis induces type IIx/b fiber atrophy in rat diaphragm and skeletal muscle, and decreases IGF-I mRNA in the liver but not in muscle. J. Hepatol. 29: 241–249.CrossRefGoogle Scholar
  31. 31.
    Dejeans, N., S. Auclair, S. Chauvet, D. Milenkovic, and A. Mazur (2009) Transcriptomic analysis of aorta from a short-term high-fat diet fed mouse reveals changes in the expression of vessel structure genes. J. Physiol. Pharmacol. 1: 37–45.Google Scholar
  32. 32.
    Huxley, H. and J. Hanson (1954) Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation. Nature 173: 973–976.CrossRefGoogle Scholar
  33. 33.
    Zierath, J. R. and J. A. Hawley (2004) Skeletal muscle fiber type: influence on contractile and metabolic properties. PLoS Biol. 2: e348.CrossRefGoogle Scholar
  34. 34.
    Brotto, M. A., B. J. Biesiadecki, L. S. Brotto, T. M. Nosek, and J. P. Jin (2006) Coupled expression of troponin T and troponin I isoforms in single skeletal muscle fibers correlates with contractility. Am. J. Physiol. Cell. Physiol. 290: 567–576.CrossRefGoogle Scholar
  35. 35.
    Wang, Y. X., C. L. Zhang, R. T. Yu, H. K. Cho, M. C. Nelson, C. R. Bayuga-Ocampo, J. Ham, H. Kang, and R. M. Evans (2004) Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol. 2: e294.CrossRefGoogle Scholar
  36. 36.
    Bjorntorp, P. (1985) Regional patterns of fat distribution. Ann. Intern. Med. 103: 994–995.CrossRefGoogle Scholar
  37. 37.
    Petridou, A., S. Tsalouhidou, G. Tsalis, T. Schulz, H. Michna, and V. Mougios (2007) Long-term exercise increases the DNA binding activity of peroxisome proliferator-activated receptor gamma in rat adipose tissue. Metabolism. 56: 1029–1036.CrossRefGoogle Scholar
  38. 38.
    Kawamura, T., K. Yoshida, A. Sugawara, M. Nagasaka, N. Mori, K. Takeuchi, and M. Kohzuki (2004) Regulation of skeletal muscle peroxisome proliferator-activated receptor gamma expression by exercise and angiotensin-converting enzyme inhibition in fructose-fed hypertensive rats. Hypertens. Res. 27: 61–70.CrossRefGoogle Scholar
  39. 39.
    Wikk, A. (2008) Estrogen receptors in skeletal muscle, expression and activation. pp. 1–49. Ph. D. Thesis. Karolinska Institute, Sweden.Google Scholar
  40. 40.
    Amin, R. H., S. T. Mathews, H. S. Camp, L. Ding, and T. Leff (2010) Selective activation of PPARgamma in skeletal muscle induces endogenous production of adiponectin and protects mice from diet-induced insulin resistance. Am. J. Physiol. Endocrinol. Metab. 298: 28–37.CrossRefGoogle Scholar
  41. 41.
    Sato, H., H. Sugai, H. Kurosaki, M. Ishikawa, A. Funaki, Y. Kimura, and K. Ueno (2013) The effect of sex hormones on peroxisome proliferator-activated receptor gamma expression and activity in mature adipocytes. Biol. Pharm. Bull. 36: 564–573.CrossRefGoogle Scholar
  42. 42.
    St John, L. C., D. C. Rule, D. A. Knabe, H. J. Mersmann, and S. B. Smith (1987) Fatty acid-binding protein activity in tissues from pigs fed diets containing 0 and 20% high oleate oil. J. Nutr. 117: 2021–2026.Google Scholar
  43. 43.
    Miller, W. C., R. C. Hickson, and N. M. Bass (1988) Fatty acid binding proteins in the three types of rat skeletal muscle. Proc. Soc. Exp. Biol. Med. 189: 183–188.CrossRefGoogle Scholar
  44. 44.
    Coort, S. L., W. A. Coumans, A. Bonen, G. J. van der Vusse, J. F. Glatz, and J. J. Luiken (2005) Divergent effects of rosiglitazone on protein-mediated fatty acid uptake in adipose and in muscle tissues of Zucker rats. J. Lipid Res. 46: 1295–1302.CrossRefGoogle Scholar
  45. 45.
    Langfort, J., M. Donsmark, T. Ploug, C. Holm, and H. Galbo (2003) Hormone-sensitive lipase in skeletal muscle: Regulatory mechanisms. Acta Physiol. Scand. 178: 397–403.CrossRefGoogle Scholar
  46. 46.
    Jensen, M. D., M. L. Martin, P. E. Cryer, and L. R. Roust (1994) Effects of estrogen on free fatty acid metabolism in humans. Am. J. Physiol. 266: 914–920.Google Scholar
  47. 47.
    Pedersen, S. B., K. Kristensen, P. A. Hermann, J. A. Katzenellenbogen, and B. Richelsen (2004) Estrogen controls lipolysis by up-regulating alpha2A-adrenergic receptors directly in human adipose tissue through the estrogen receptor alpha. Implications for the female fat distribution. J. Clin. Endocrinol. Metab. 89: 1869–1878.CrossRefGoogle Scholar
  48. 48.
    Park, S. Y., H. J. Kim, S. Wang, T. Higashimori, J. Dong, Y. J. Kim, G. Cline, H. Li, M. Prentki, G. I. Shulman, G. A. Mitchell, and J. K. Kim (2005) Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart. Am. J. Physiol. Endocrinol. Metab. 289: 30–39.CrossRefGoogle Scholar
  49. 49.
    Holm, C., T. Osterlund, H. Laurell, and J. A. Contreras (2000) Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Annu. Rev. Nutr. 20: 365–393.CrossRefGoogle Scholar
  50. 50.
    Tan, M. H., T. Sata, and R. J. Havel (1977) The significance of lipoprotein lipase in rat skeletal muscles. J. Lipid. Res. 18: 363–370.Google Scholar
  51. 51.
    Pei, Z., P. Fraisl, J. Berger, Z. Jia, S. Forss-Petter, and P. A. Watkins (2004) Mouse very long-chain Acyl-CoA synthetase 3/fatty acid transport protein 3 catalyzes fatty acid activation but not fatty acid transport in MA-10 cells. J. Biol. Chem. 279: 54454–54462.CrossRefGoogle Scholar
  52. 52.
    Soupene, E. and F. A. Kuypers (2008) Mammalian long-chain acyl-CoA synthetases. Exp. Biol. Med. 233: 507–521.CrossRefGoogle Scholar
  53. 53.
    Berke, B. M. and M. L. Kaplan (1983) Effects of high fat and high carbohydrate diets on development of hepatic and adipose lipogenesis in fa/fa and non-fa/fa rats. J. Nutr. 113: 820–834.Google Scholar
  54. 54.
    Shillabeer, G., J. Hornford, J. M. Forden, N. C. Wong, and D. C. Lau (1990) Hepatic and adipose tissue lipogenic enzyme mRNA levels are suppressed by high fat diets in the rat. J. Lipid Res. 31: 623–631.Google Scholar
  55. 55.
    Lupu, R. and J. A. Menendez (2006) Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators? Endocrinol. 147: 4056–4066.CrossRefGoogle Scholar
  56. 56.
    Demonacos, C. V., N. Karayanni, E. Hatzoglou, C. Tsiriyiotis, D. A. Spandidos, and C. E. Sekeris (1996) Mitochondrial genes as sites of primary action of steroid hormones. Steroids. 61: 226–232.CrossRefGoogle Scholar
  57. 57.
    Barclay, C. J., R. C. Woledge, and N. A. Curtin (2007) Energy turnover for Ca2+ cycling in skeletal muscle. J. Muscle. Res. Cell. Motil. 28: 259–274.CrossRefGoogle Scholar
  58. 58.
    Hojlund, K., K. Wrzesinski, P. M. Larsen, S. J. Fey, P. Roepstorff, A. Handberg, F. Dela, J. Vinten, J. G. McCormack, C. Reynet, and H. Beck-Nielsen (2003) Proteome analysis reveals phosphorylation of ATP synthase beta -subunit in human skeletal muscle and proteins with potential roles in type 2 diabetes. J. Biol. Chem. 278: 10436–10442.CrossRefGoogle Scholar
  59. 59.
    Finocchiaro, G., M. Ito, Y. Ikeda, and K. Tanaka (1988) Molecular cloning and nucleotide sequence of cDNAs encoding the alpha-subunit of human electron transfer flavoprotein. J. Biol. Chem. 263: 15773–15780.Google Scholar
  60. 60.
    Miller, W. C., G. R. Bryce, and R. K. Conlee (1984) Adaptations to a high-fat diet that increase exercise endurance in male rats. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 56: 78–83.Google Scholar
  61. 61.
    Jonsson, D. (2007) The biological role of the female sex hormone estrogen in the periodontium-studies on human periodontal ligament cells. Swed. Dent. J. Suppl. 11–54.Google Scholar
  62. 62.
    Heine, P. A., J. A. Taylor, G. A. Iwamoto, D. B. Lubahn, and P. S. Cooke (2000) Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc. Natl. Acad. Sci. U S A. 97: 12729–12734.CrossRefGoogle Scholar
  63. 63.
    Barros, R. P., U. F. Machado, M. Warner, and J. A. Gustafsson (2006) Muscle GLUT4 regulation by estrogen receptors ERbeta and ERalpha. Proc. Natl. Acad. Sci. U S A. 103: 1605–1608.CrossRefGoogle Scholar
  64. 64.
    Lin, H. Y., Q. Xu, S. Yeh, R. S. Wang, J. D. Sparks, and C. Chang (2005) Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor. Diabetes. 54: 1717–1725.CrossRefGoogle Scholar
  65. 65.
    D’Eon, T. M., S. C. Souza, M. Aronovitz, M. S. Obin, S. K. Fried, and A. S. Greenberg (2005) Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways. J. Biol. Chem. 280: 35983–35991.CrossRefGoogle Scholar
  66. 66.
    Zheng, D., P. S. MacLean, S. C. Pohnert, J. B. Knight, A. L. Olson, W. W. Winder, and G. L. Dohm (2001) Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. J. Appl. Physiol. 91: 1073–1083.Google Scholar
  67. 67.
    Hisamoto, K., M. Ohmichi, H. Kurachi, J. Hayakawa, Y. Kanda, Y. Nishio, K. Adachi, K. Tasaka, E. Miyoshi, N. Fujiwara, N. Taniguchi, and Y. Murata (2001) Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells. J. Biol. Chem. 276: 3459–3467.CrossRefGoogle Scholar
  68. 68.
    Kern, M., J. A. Wells, J. M. Stephens, C. W. Elton, J. E. Friedman, E. B. Tapscott, P. H. Pekala, and G. L. Dohm (1990) Insulin responsiveness in skeletal muscle is determined by glucose transporter (Glut4) protein level. Biochem. J. 270: 397–400.Google Scholar
  69. 69.
    Krook, A., Y. Kawano, X. M. Song, S. Efendiæ, R. A. Roth, H. Wallberg-Henriksson, and J. R. Zierath (1997) Improved glucose tolerance restores insulin-stimulated Akt kinase activity and glucose transport in skeletal muscle from diabetic Goto-Kakizaki rats. Diabetes. 46: 2110–2114.CrossRefGoogle Scholar
  70. 70.
    Huang, W., R. Bansode, M. Mehta, and K. D. Mehta (2009) Loss of protein kinase C beta function protects mice against diet-induced obesity and development of hepatic steatosis and insulin resistance. Hepatol. 49: 1525–1536.CrossRefGoogle Scholar
  71. 71.
    Insenser, M., R. Montes-Nieto, N. Vilarrasa, A. Lecube, R. Simo, J. Vendrell, and H. F. Escobar-Morreale (2012) A nontargeted proteomic approach to the study of visceral and subcutaneous adipose tissue in human obesity. Mol. Cell. Endocrinol. 363: 10–19.CrossRefGoogle Scholar
  72. 72.
    Ordonez, P., M. Moreno, A. Alonso, P. Llaneza, F. Diaz, and C. Gonzalez (2008) 17beta-Estradiol and/or progesterone protect from insulin resistance in STZ-induced diabetic rats. J. Steroid Biochem. Mol. Biol. 111: 287–294.CrossRefGoogle Scholar
  73. 73.
    Ploug, T., H. Galbo, and E. A. Richter (1984) Increased muscle glucose uptake during contractions: no need for insulin. Am. J. Physiol. 247: 726–731.Google Scholar
  74. 74.
    Marette, A., J. M. Richardson, T. Ramlal, T.W. Balon, M. Vranic, J. E. Pessin, and A. Klip (1992) Abundance, localization, and insulin-induced translocation of glucose transporters in red and white muscle. Am. J. Physiol. 263: 443–452.Google Scholar

Copyright information

© The Korean Society for Biotechnology and Bioengineering and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kanikkai Raja Aseer
    • 1
  • Sang Woo Kim
    • 1
  • Dong Gun Lee
    • 2
  • Jong Won Yun
    • 1
  1. 1.Department of BiotechnologyDaegu UniversityKyungsanKorea
  2. 2.School of Life Sciences, College of Natural SciencesKyungpook National UniversityDaeguKorea

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