Skip to main content

Advertisement

SpringerLink
Log in

Enhanced skeletal muscle glycogen repletion after endurance exercise is associated with higher plasma insulin and skeletal muscle hexokinase 2 protein levels in mice: comparison of level running and downhill running model

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

To identify factors that influence post-exercise muscle glycogen repletion, we compared the glycogen recovery after level running with downhill running, an experimental model of impaired post-exercise glycogen recovery. Male Institute of Cancer Research (ICR) mice performed endurance level running (no inclination) or downhill running (−5° inclination) on a treadmill. In Experiment 1, to determine whether these two types of exercise resulted in different post-exercise glycogen repletion patterns, tissues were harvested immediately post-exercise or 2 days post-exercise. Compared to the control (sedentary) group, level running induced significant glycogen supercompensation in the soleus muscle at 2 days post-exercise (p = 0.002). Downhill running did not induce glycogen supercompensation. In Experiment 2, mice were orally administered glucose 1 day post-exercise; this induced glycogen supercompensation in soleus and plantaris muscle only in the level running group (soleus: p = 0.005, plantaris: p = 0.003). There were significant positive main effects of level running compared to downhill running on the plasma insulin (p = 0.017) and C-peptide concentration (p = 0.011). There was no difference in the glucose transporter 4 level or the phosphorylated states of proteins related to insulin signaling and metabolism in skeletal muscle. The level running group showed significantly higher hexokinase 2 (HK2) protein content in both soleus (p = 0.046) and plantaris muscles (p =0.044) at 1 day after exercise compared to the downhill running group. Our findings suggest that post-exercise skeletal muscle glycogen repletion might be partly influenced by plasma insulin and skeletal muscle HK2 protein levels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. Aoi W, Naito Y, Tokuda H, Tanimura Y, Oya-Ito T, Yoshikawa T (2012) Exercise-induced muscle damage impairs insulin signaling pathway associated with IRS-1 oxidative modification. Physiol Res 61:81–88. https://doi.org/10.33549/physiolres.932239

    Article  CAS  PubMed  Google Scholar 

  2. Armstrong RB, Taylor CR (1993) Glycogen loss in rat muscles during locomotion on different inclines. J Exp Biol 176:135–144

    Article  CAS  Google Scholar 

  3. Armstrong RB, Laughlin MH, Rome L, Taylor CR (1983) Metabolism of rats running up and down an incline. J Appl Physiol 55:518–521. https://doi.org/10.1152/jappl.1983.55.2.518

    Article  CAS  PubMed  Google Scholar 

  4. Armstrong RB, Ogilvie RW, Schwane JA (1983) Eccentric exercise-induced injury to rat skeletal muscle. J Appl Physiol 54:80–93. https://doi.org/10.1152/jappl.1983.54.1.80

    Article  CAS  PubMed  Google Scholar 

  5. Asp S, Daugaard JR, Richter EA (1995) Eccentric exercise decreases glucose transporter GLUT4 protein in human skeletal muscle. J Physiol 482:705–712. https://doi.org/10.1113/jphysiol.1995.sp020553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Asp S, Kristiansen S, Richter EA (1995) Eccentric muscle damage transiently decreases rat skeletal muscle GLUT-4 protein. J Appl Physiol 79:1338–1345. https://doi.org/10.1152/jappl.1995.79.4.1338

    Article  CAS  PubMed  Google Scholar 

  7. Asp S, Daugaard JR, Kristiansen S, Kiens B, Richter EA (1996) Eccentric exercise decreases maximal insulin action in humans: muscle and systemic effects. J Physiol 494(Pt 3):891–898. https://doi.org/10.1113/jphysiol.1996.sp021541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Asp S, Rohde T, Richter EA (1997) Impaired muscle glycogen resynthesis after a marathon is not caused by decreased muscle GLUT-4 content. J Appl Physiol 83:14821485. https://doi.org/10.1152/jappl.1997.83.5.1482

    Article  Google Scholar 

  9. Asp S, Daugaard JR, Rohde T, Adamo K, Graham T (1999) Muscle glycogen accumulation after a marathon: roles of fiber type and pro- and macroglycogen. J Appl Physiol 86:474–478. https://doi.org/10.1152/jappl.1999.86.2.474

    Article  CAS  PubMed  Google Scholar 

  10. Bergström J, Hultman E (1966) Muscle glycogen synthesis after exercise: an enhancing factor localized to the muscle cells in man. Nature 210:309–310. https://doi.org/10.1038/210309a0

    Article  PubMed  Google Scholar 

  11. Burke LM, van Loon LJC, Hawley JA (2017) Postexercise muscle glycogen resynthesis in humans. J Appl Physiol 122:1055–1067. https://doi.org/10.1152/japplphysiol.00860.2016

    Article  CAS  PubMed  Google Scholar 

  12. Costill DL, Pascoe DD, Fink WJ, Robergs RA, Barr SI, Pearson D (1990) Impaired muscle glycogen resynthesis after eccentric exercise. J Appl Physiol 69:46–50. https://doi.org/10.1152/jappl.1990.69.1.46

    Article  CAS  PubMed  Google Scholar 

  13. Del Aguila LF, Krishnan RK, Ulbrecht JS, Farrell PA, Correll PH, Lang CH, Zierath JR, Kirwan JP (2000) Muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase in human skeletal muscle. Am J Physiol Endocrinol Metab 279:E206–E212. https://doi.org/10.1152/ajpendo.2000.279.1.E206

    Article  PubMed  Google Scholar 

  14. Derave W, Lund S, Holman GD, Wojtaszewski J, Pedersen O, Richter EA (1999) Contraction-stimulated muscle glucose transport and GLUT-4 surface content are dependent on glycogen content. Am J Phys 277:E1103–E1110. https://doi.org/10.1152/ajpendo.1999.277.6.E1103

    Article  CAS  Google Scholar 

  15. Doyle JA, Sherman WM, Strauss RL (1993) Effects of eccentric and concentric exercise on muscle glycogen replenishment. J Appl Physiol 74:1848–1855. https://doi.org/10.1152/jappl.1993.74.4.1848

    Article  CAS  PubMed  Google Scholar 

  16. Flores-Opazo M, McGee SL, Hargreaves M (2020) Exercise and GLUT4. Exerc Sport Sci Rev 48:110–118. https://doi.org/10.1249/JES.0000000000000224

    Article  PubMed  Google Scholar 

  17. Hansen PA, Nolte LA, Chen MM, Holloszy JO (1998) Increased GLUT-4 translocation mediates enhanced insulin sensitivity of muscle glucose transport after exercise. J Appl Physiol 85:1218–1222. https://doi.org/10.1152/jappl.1998.85.4.1218

    Article  CAS  PubMed  Google Scholar 

  18. Hawley JA, Leckey JJ (2015) Carbohydrate Dependence During Prolonged, Intense Endurance Exercise. Sports Med 45(Suppl 1):S5–S12. https://doi.org/10.1007/s40279-015-0400-1

    Article  PubMed  Google Scholar 

  19. Hickner RC, Fisher JS, Hansen PA, Racette SB, Mier CM, Turner MJ, Holloszy JO (1997) Muscle glycogen accumulation after endurance exercise in trained and untrained individuals. J Appl Physiol 83:897–903. https://doi.org/10.1152/jappl.1997.83.3.897

    Article  CAS  PubMed  Google Scholar 

  20. Hingst JR, Bruhn L, Hansen MB, Rosschou MF, Birk JB, Fentz J, Foretz M, Viollet B, Sakamoto K, Færgeman NJ, Havelund JF, Parker BL, James DE, Kiens B, Richter EA, Jensen J, Wojtaszewski JFP (2018) Exercise-induced molecular mechanisms promoting glycogen supercompensation in human skeletal muscle. Mol Metab 16:24–34. https://doi.org/10.1016/j.molmet.2018.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Irimia JM, Rovira J, Nielsen JN, Guerrero M, Wojtaszewski JFP, Cussó R (2012) Hexokinase 2, glycogen synthase and phosphorylase play a key role in muscle glycogen supercompensation. PLoS One 7:e42453. https://doi.org/10.1371/journal.pone.0042453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Krishnan RK, Hernandez JM, Williamson DL, O’Gorman DJ, Evans WJ, Kirwan JP (1998) Age-related differences in the pancreatic beta-cell response to hyperglycemia after eccentric exercise. Am J Phys 275:E463–E470. https://doi.org/10.1152/ajpendo.1998.275.3.E463

    Article  CAS  Google Scholar 

  23. Kristiansen S, Jones J, Handberg A, Dohm DL, Richher EA (1997) Eccentric contractions decrease glucose transporter transcription rate, mRNA, and protein in skeletal muscle. Am J Phys 272:C1734–C1738. https://doi.org/10.1152/ajpcell.1997.272.5.C1734

    Article  CAS  Google Scholar 

  24. Krustrup P, Ortenblad N, Nielsen J, Nybo L, Gunnarsson TP, Iaia FM, Madsen K, Stephens F, Greenhaff P, Bangsbo J (2011) Maximal voluntary contraction force, SR function and glycogen resynthesis during the first 72 h after a high-level competitive soccer game. Eur J Appl Physiol 111:2987–2995. https://doi.org/10.1007/s00421-011-1919-y

    Article  PubMed  Google Scholar 

  25. Lo S, Russell JC, Taylor AW (1970) Determination of glycogen in small tissue samples. J Appl Physiol 28:234–236. https://doi.org/10.1152/jappl.1970.28.2.234

    Article  CAS  PubMed  Google Scholar 

  26. Mandarino LJ, Printz RL, Cusi KA, Kinchington P, O’Doherty RM, Osawa H, Sewell C, Consoli A, Granner DK, DeFronzo RA (1995) Regulation of hexokinase II and glycogen synthase mRNA, protein, and activity in human muscle. Am J Phys 269:E701–E708. https://doi.org/10.1152/ajpendo.1995.269.4.E701

    Article  CAS  Google Scholar 

  27. Mehta VK, Hao W, Brooks-Worrell BM, Palmer JP (1994) Low-dose interleukin 1 and tumor necrosis factor individually stimulate insulin release but in combination cause suppression. Eur J Endocrinol 130:208–214. https://doi.org/10.1530/eje.0.1300208

    Article  CAS  PubMed  Google Scholar 

  28. Nakatani A, Han DH, Hansen PA, Nolte LA, Host HH, Hickner RC, Holloszy JO (1997) Effect of endurance exercise training on muscle glycogen supercompensation in rats. J Appl Physiol 82:711–715. https://doi.org/10.1152/jappl.1997.82.2.711

    Article  CAS  PubMed  Google Scholar 

  29. Overmyer KA, Thonusin C, Qi NR, Burant CF, Evans CR (2015) Impact of anesthesia and euthanasia on metabolomics of mammalian tissues: studies in a C57BL/6J mouse model. PLoS One 10:e0117232. https://doi.org/10.1371/journal.pone.0117232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Roberts DJ, Miyamoto S (2015) Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ 22:248–257. https://doi.org/10.1038/cdd.2014.173

    Article  CAS  PubMed  Google Scholar 

  31. Stephens FB, Norton L, Jewell K, Chokkalingam K, Parr T, Tsintzas K (2010) Basal and insulin-stimulated pyruvate dehydrogenase complex activation, glycogen synthesis and metabolic gene expression in human skeletal muscle the day after a single bout of exercise. Exp Physiol 95:808–818. https://doi.org/10.1113/expphysiol.2009.051367

    Article  CAS  PubMed  Google Scholar 

  32. Takahashi Y, Matsunaga Y, Banjo M, Takahashi K, Sato Y, Seike K, Nakano S, Hatta H (2019) Effects of Nutrient Intake Timing on Post-Exercise Glycogen Accumulation and its Related Signaling Pathways in Mouse Skeletal Muscle. Nutrients 11. https://doi.org/10.3390/nu11112555

  33. Tanaka K, Kawano T, Tomino T, Kawano H, Okada T, Oshita S, Takahashi A, Nakaya Y (2009) Mechanisms of impaired glucose tolerance and insulin secretion during isoflurane anesthesia. Anesthesiology 111:1044–1051. https://doi.org/10.1097/ALN.0b013e3181bbcb0d

    Article  CAS  PubMed  Google Scholar 

  34. Villar-Palasí C, Guinovart JJ (1997) The role of glucose 6-phosphate in the control of glycogen synthase. FASEB J 11:544–558. https://doi.org/10.1096/fasebj.11.7.9212078

    Article  PubMed  Google Scholar 

  35. Vogt C, Ardehali H, Iozzo P, Yki-Järvinen H, Koval J, Maezono K, Pendergrass M, Printz R, Granner D, DeFronzo R, Mandarino L (2000) Regulation of hexokinase II expression in human skeletal muscle in vivo. Metabolism 49:814–818. https://doi.org/10.1053/meta.2000.6245

    Article  CAS  PubMed  Google Scholar 

  36. Wasserman DH, Kang L, Ayala JE, Fueger PT, Lee-Young RS (2011) The physiological regulation of glucose flux into muscle in vivo. J Exp Biol 214:254–262. https://doi.org/10.1242/jeb.048041

    Article  CAS  PubMed  Google Scholar 

  37. Weber FE, Pette D (1990) Changes in free and bound forms and total amount of hexokinase isozyme II of rat muscle in response to contractile activity. Eur J Biochem 191:85–90. https://doi.org/10.1111/j.1432-1033.1990.tb19096.x

    Article  CAS  PubMed  Google Scholar 

  38. Widrick JJ, Costill DL, McConell GK, Anderson DE, Pearson DR, Zachwieja JJ (1992) Time course of glycogen accumulation after eccentric exercise. J Appl Physiol 72:1999–2004. https://doi.org/10.1152/jappl.1992.72.5.1999

    Article  CAS  PubMed  Google Scholar 

  39. Windeløv JA, Pedersen J, Holst JJ (2016) Use of anesthesia dramatically alters the oral glucose tolerance and insulin secretion in C57Bl/6 mice. Phys Rep 4:e12824. https://doi.org/10.14814/phy2.12824

    Article  CAS  Google Scholar 

  40. Wojtaszewski JF, Hansen BF, Gade, Kiens B, Markuns JF, Goodyear LJ, Richter EA (2000) Insulin signaling and insulin sensitivity after exercise in human skeletal muscle. Diabetes 49:325–331. https://doi.org/10.2337/diabetes.49.3.325

    Article  CAS  PubMed  Google Scholar 

  41. Zachwieja JJ, Costill DL, Pascoe DD, Robergs RA, Fink WJ (1991) Influence of muscle glycogen depletion on the rate of resynthesis. Med Sci Sports Exerc 23:44–48. https://doi.org/10.1249/00005768-199101000-00008

    Article  CAS  PubMed  Google Scholar 

  42. Zawadzki KM, Yaspelkis BB 3rd, Ivy JL (1992) Carbohydrate-protein complex increases the rate of muscle glycogen storage after exercise. J Appl Physiol 72:1854–1859. https://doi.org/10.1152/jappl.1992.72.5.1854

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research was financially supported by Grant-in-Aid for Young Scientists (18K17853) from the Japan Society for the Promotion of Science.

Author information

Authors and Affiliations

  1. Department of Sports Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro, Tokyo, 153-8902, Japan

    Yumiko Takahashi, Juli Sarkar, Jumpei Yamada, Yutaka Matsunaga, Mai Banjo, Ryo Sakaguchi, Terunaga Shinya & Hideo Hatta

  2. Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, 1-5-1 Chofugaoka, Chofu, Tokyo, 182-8585, Japan

    Yudai Nonaka

Authors
  1. Yumiko Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juli Sarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jumpei Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yutaka Matsunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yudai Nonaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mai Banjo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ryo Sakaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Terunaga Shinya
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hideo Hatta
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, YT, JS, and HH; data curation, YT, JS, JY, YM, MB, RS, and TS; formal analysis, YT, JS, and JY; data interpretation; YT, JS, YM, YN, and HH; writing—original draft preparation, YT, JS, and HH. All authors reviewed and then approved the final version of the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Yumiko Takahashi.

Ethics declarations

Ethics approval

All procedures involving animals were conducted in accordance with the ethical standards of the Committee on Animal Care and Use, The University of Tokyo; all experimental protocols were approved by this committee (approval no. 24-4).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key Points

• We compared two running models to find factors stimulating glycogen recovery.

• Greater glycogen recovery was collateral with higher muscle HK2 and plasma insulin.

• Greater glycogen recovery was not accompanied with activated insulin signaling.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takahashi, Y., Sarkar, J., Yamada, J. et al. Enhanced skeletal muscle glycogen repletion after endurance exercise is associated with higher plasma insulin and skeletal muscle hexokinase 2 protein levels in mice: comparison of level running and downhill running model. J Physiol Biochem 77, 469–480 (2021). https://doi.org/10.1007/s13105-021-00806-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-021-00806-z

Keywords

Search

Navigation