Skip to main content
SpringerLink
Log in

Effect of hypobaric hypoxia on the fiber type transition of skeletal muscle: a synergistic therapy of exercise preconditioning with a nanocurcumin formulation

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

Abstract

Hypobaric hypoxia (HH) leads to various adverse effects on skeletal muscles, including atrophy and reduced oxidative work capacity. However, the effects of HH on muscle fatigue resistance and myofiber remodeling are largely unexplored. Therefore, the present study aimed to explore the impact of HH on slow-oxidative fibers and to evaluate the ameliorative potential of exercise preconditioning and nanocurcumin formulation on muscle anti-fatigue ability. C2C12 cells (murine myoblasts) were used to assess the effect of hypoxia (0.5%, 24 h) with and without the nanocurcumin formulation (NCF) on myofiber phenotypic conversion. To further validate this hypothesis, male Sprague Dawley rats were exposed to a simulated HH (7620 m) for 7 days, along with NCF administration and/or exercise training. Both in vitro and in vivo studies revealed a significant reduction in slow-oxidative fibers (p < 0.01, 61% vs. normoxia control) under hypoxia. There was also a marked decrease in exhaustion time (p < 0.01, 65% vs. normoxia) in hypoxia control rats, indicating a reduced work capacity. Exercise preconditioning along with NCF supplementation significantly increased the slow-oxidative fiber proportion and exhaustion time while maintaining mitochondrial homeostasis. These findings suggest that HH leads to an increased transition of slow-oxidative fibers to fast glycolytic fibers and increased muscular fatigue. Administration of NCF in combination with exercise preconditioning restored this myofiber remodeling and improved muscle anti-fatigue ability.

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
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Data Availability

N/A

References

  1. Abdelmalki A, Fimbel S, Mayet-Sornay MH et al (1996) Aerobic capacity and skeletal muscle properties of normoxic and hypoxic rats in response to training. Pflugers Arch 431(5):671–679

    Article  CAS  PubMed  Google Scholar 

  2. Agrawal A, Rathore R, Kumar R et al (2018) Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy. PLoS ONE 13(9):e0204283

    Article  PubMed  PubMed Central  Google Scholar 

  3. Agrawal A, Rathore R, Kumar R et al (2020) Redox modification of ryanodine receptor contributes to impaired Ca(2+) homeostasis and exacerbates muscle atrophy under high altitude. Free Radic Biol Med 160:643–656

    Article  CAS  PubMed  Google Scholar 

  4. Al-Dashti YA, Holt RR, Stebbins CL et al (2018) Dietary flavanols: a review of select effects on vascular function, blood pressure, and exercise performance. J Am Coll Nutr 37(7):553–567

    Article  PubMed  Google Scholar 

  5. Avci G, Kadioglu H, Sehirli AO et al (2012) Curcumin protects against ischemia/reperfusion injury in rat skeletal muscle. J Surg Res 172(1):e39-46

    Article  CAS  PubMed  Google Scholar 

  6. Bassel-Duby R, Olson EN (2006) Signaling pathways in skeletal muscle remodeling. Annu Rev Biochem 75:19–37

    Article  CAS  PubMed  Google Scholar 

  7. Bo H, Wang YH, Li HY et al (2008) Endurance training attenuates the bioenergetics alterations of rat skeletal muscle mitochondria submitted to acute hypoxia: role of ROS and UCP3. Sheng Li Xue Bao 60(6):767–776

    CAS  PubMed  Google Scholar 

  8. Booth FW, Ruegsegger GN, Toedebusch RG et al (2015) Endurance exercise and the regulation of skeletal muscle metabolism. Prog Mol Biol Transl Sci 135:129–151

    Article  PubMed  Google Scholar 

  9. Bottinelli R, Reggiani C (2000) Human skeletal muscle fibers: molecular and functional diversity. Prog Biophys Mol Biol 73(2–4):195–262

    Article  CAS  PubMed  Google Scholar 

  10. Bradwell AR, Dykes PW, Coote JH et al (1986) Effect of acetazolamide on exercise performance and muscle mass at high altitude. Lancet 1(8488):1001–1005

    Article  CAS  PubMed  Google Scholar 

  11. Canto C, Gerhart-Hines Z, Feige JN et al (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458(7241):1056–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chaillou T (2018) Skeletal muscle fiber type in hypoxia: adaptation to high-altitude exposure and under conditions of pathological hypoxia. Front Physiol 9:1450

    Article  PubMed  PubMed Central  Google Scholar 

  13. Chaillou T, Koulmann N, Meunier A et al (2014) Effect of hypoxia exposure on the recovery of skeletal muscle phenotype during regeneration. Mol Cell Biochem 390(1–2):31–40

    Article  CAS  PubMed  Google Scholar 

  14. Chalkiadaki A, Igarashi M, Nasamu AS et al (2014) 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):e1004490

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chaudhary P, Suryakumar G, Prasad R et al (2012) Chronic hypobaric hypoxia-mediated skeletal muscle atrophy: role of ubiquitin-proteasome pathway and calpains. Mol Cell Biochem 364(1–2):101–113

    Article  CAS  PubMed  Google Scholar 

  16. Chaudhary P, Suryakumar G, Sharma YK et al (2012) Differential response of the gastrocnemius and soleus muscles of rats to chronic hypobaric hypoxia. Aviat Space Environ Med 83(11):1037–1043

    Article  PubMed  Google Scholar 

  17. Chen X, Liang D, Huang Z et al (2021) Quercetin regulates skeletal muscle fiber type switching via adiponectin signaling. Food Funct 12(6):2693–2702

    Article  CAS  PubMed  Google Scholar 

  18. Chen X, Zhang M, Xue Y et al (2022) Effect of dietary L-theanine supplementation on skeletal muscle fiber type transformation in vivo. J Nutr Biochem 99:108859

    Article  CAS  PubMed  Google Scholar 

  19. Chicco AJ, Le CH, Gnaiger E et al (2018) Adaptive remodeling of skeletal muscle energy metabolism in high-altitude hypoxia: lessons from AltitudeOmics. J Biol Chem 293(18):6659–6671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chitra L, Boopathy R (2013) Adaptability to hypobaric hypoxia is facilitated through mitochondrial bioenergetics: an in vivo study. Br J Pharmacol 169(5):1035–1047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dei Cas M, Ghidoni R (2019) Dietary curcumin: correlation between bioavailability and health potential. Nutrients 11(9):2147

    Article  PubMed  PubMed Central  Google Scholar 

  22. Edwards LM, Murray AJ, Tyler DJ et al (2010) The effect of high-altitude on human skeletal muscle energetics: P-MRS results from the Caudwell Xtreme Everest expedition. PLoS ONE 5(5):e10681

    Article  PubMed  PubMed Central  Google Scholar 

  23. Flora G, Gupta D, Tiwari A (2013) Nanocurcumin: a promising therapeutic advancement over native curcumin. Crit Rev Ther Drug Carrier Syst 30(4):331–368

    Article  CAS  PubMed  Google Scholar 

  24. Hirabayashi T, Nakanishi R, Tanaka M et al (2021) Reduced metabolic capacity in fast and slow skeletal muscle via oxidative stress and the energy-sensing of AMPK/SIRT1 in malnutrition. Physiol Rep 9(5):e14763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hoppeler H, Klossner S, Vogt M (2008) Training in hypoxia and its effects on skeletal muscle tissue. Scand J Med Sci Sports 18(Suppl 1):38–49

    Article  PubMed  Google Scholar 

  26. Hoppeler H, Vogt M (2001) Muscle tissue adaptations to hypoxia. J Exp Biol 204(Pt 18):3133–3139

    Article  CAS  PubMed  Google Scholar 

  27. Hoppeler H, Vogt M, Weibel ER et al (2003) Response of skeletal muscle mitochondria to hypoxia. Exp Physiol 88(1):109–119

    Article  CAS  PubMed  Google Scholar 

  28. Howald H, Hoppeler H (2003) Performing at extreme altitude: muscle cellular and subcellular adaptations. Eur J Appl Physiol 90(3–4):360–364

    Article  PubMed  Google Scholar 

  29. Hwang PS, Machek SB, Cardaci TD et al (2020) Effects of pyrroloquinoline quinone (PQQ) supplementation on aerobic exercise performance and indices of mitochondrial biogenesis in untrained men. J Am Coll Nutr 39(6):547–556

    Article  CAS  PubMed  Google Scholar 

  30. Itoh K, Moritani T, Ishida K et al (1990) Hypoxia-induced fiber type transformation in rat hindlimb muscles. Histochemical and electromechanical changes. Eur J Appl Physiol Occup Physiol 60(5):331–336

    Article  CAS  PubMed  Google Scholar 

  31. Jacobs RA, Boushel R, Wright-Paradis C et al (2013) Mitochondrial function in human skeletal muscle following high-altitude exposure. Exp Physiol 98(1):245–255

    Article  CAS  PubMed  Google Scholar 

  32. Jezek P, Holendova B, Plecita-Hlavata L (2020) Redox signaling from mitochondria: signal propagation and its targets. Biomolecules 10(1):93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kushwaha AD, Saraswat D (2022) A nanocurcumin and pyrroloquinoline quinone formulation prevent hypobaric hypoxia-induced skeletal muscle atrophy by modulating NF-kappaB signaling pathway. High Alt Med Biol 2022(3):249–263

    Google Scholar 

  34. Liang D, Zhuo Y, Guo Z et al (2020) SIRT1/PGC-1 pathway activation triggers autophagy/mitophagy and attenuates oxidative damage in intestinal epithelial cells. Biochimie 170:10–20

    Article  CAS  PubMed  Google Scholar 

  35. Liu W, Zhai Y, Heng X et al (2016) Oral bioavailability of curcumin: problems and advancements. J Drug Target 24(8):694–702

    Article  CAS  PubMed  Google Scholar 

  36. Ma W, Zhang R, Huang Z et al (2019) PQQ ameliorates skeletal muscle atrophy, mitophagy, and fiber type transition induced by denervation via inhibition of the inflammatory signaling pathways. Ann Transl Med 7(18):440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. MacDougall JD, Green HJ, Sutton JR et al (1991) Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude. Acta Physiol Scand 142(3):421–427

    Article  CAS  PubMed  Google Scholar 

  38. Magalhaes J, Ascensao A, Soares JM et al (2005) Acute and severe hypobaric hypoxia increases oxidative stress and impairs mitochondrial function in mouse skeletal muscle. J Appl Physiol (1985) 99(4):1247–53

    Article  CAS  PubMed  Google Scholar 

  39. Mannino MH, Patel RS, Eccardt AM et al (2019) Myoglobin as a versatile peroxidase: Implications for a more important role for vertebrate striated muscle in antioxidant defense. Comp Biochem Physiol B Biochem Mol Biol 234:9–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Medeiros DM (2008) Assessing mitochondria biogenesis. Methods 46(4):288–294

    Article  CAS  PubMed  Google Scholar 

  41. Mesquita PHC, Vann CG, Phillips SM et al (2021) Skeletal muscle ribosome and mitochondrial biogenesis in response to different exercise training modalities. Front Physiol 12:725866

    Article  PubMed  PubMed Central  Google Scholar 

  42. Miura S, Kai Y, Ono M et al (2003) Overexpression of peroxisome proliferator-activated receptor gamma coactivator-1alpha downregulates GLUT4 mRNA in skeletal muscles. J Biol Chem 278(33):31385–31390

    Article  CAS  PubMed  Google Scholar 

  43. Murray AJ (2009) Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could resolve the controversies. Genome Med 1(12):117

    Article  PubMed  PubMed Central  Google Scholar 

  44. Nehra S, Bhardwaj V, Bansal A et al (2017) Combinatorial therapy of exercise-preconditioning and nanocurcumin formulation supplementation improves cardiac adaptation under hypobaric hypoxia. J Basic Clin Physiol Pharmacol 28(5):443–453

    Article  CAS  PubMed  Google Scholar 

  45. Nehra S, Bhardwaj V, Ganju L et al (2015) Nanocurcumin prevents hypoxia-induced stress in primary human ventricular cardiomyocytes by maintaining mitochondrial homeostasis. PLoS ONE 10(9):e0139121

    Article  PubMed  PubMed Central  Google Scholar 

  46. Nioka S, Moser D, Lech G et al (1998) Muscle deoxygenation in aerobic and anaerobic exercise. Adv Exp Med Biol 454:63–70

    Article  CAS  PubMed  Google Scholar 

  47. Pette D, Staron RS (1997) Mammalian skeletal muscle fiber type transitions. Int Rev Cytol 170:143–223

    Article  CAS  PubMed  Google Scholar 

  48. Pette D, Staron RS (2001) Transitions of muscle fiber phenotypic profiles. Histochem Cell Biol 115(5):359–372

    Article  CAS  PubMed  Google Scholar 

  49. Pilegaard H, Saltin B, Neufer PD (2003) Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 546(Pt 3):851–858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rahar B, Chawla S, Tulswani R et al (2019) Acute hypobaric hypoxia-mediated biochemical/metabolic shuffling and differential modulation of S1PR-SphK in cardiac and skeletal muscles. High Alt Med Biol 20(1):78–88

    Article  CAS  PubMed  Google Scholar 

  51. Rathor R, Suryakumar G, Singh SN (2021) Diet and redox state in maintaining skeletal muscle health and performance at high altitude. Free Radic Biol Med 174:305–320

    Article  CAS  PubMed  Google Scholar 

  52. Schiaffino S, Reggiani C (2011) Fiber types in mammalian skeletal muscles. Physiol Rev 91(4):1447–1531

    Article  CAS  PubMed  Google Scholar 

  53. Shome S, Talukdar AD, Choudhury MD et al (2016) Curcumin as a potential therapeutic natural product: a nanobiotechnological perspective. J Pharm Pharmacol 68(12):1481–1500

    Article  CAS  PubMed  Google Scholar 

  54. Spinazzi M, Casarin A, Pertegato V et al (2012) Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells. Nat Protoc 7(6):1235–1246

    Article  CAS  PubMed  Google Scholar 

  55. Sumi D, Kojima C, Goto K (2018) Impact of endurance exercise in hypoxia on muscle damage, inflammatory, and performance responses. J Strength Cond Res 32(4):1053–1062

    Article  PubMed  Google Scholar 

  56. Tanaka M, Mizuta K, Koba F et al (1997) Effects of exposure to hypobaric-hypoxia on body weight, muscular and hematological characteristics, and work performance in rats. Jpn J Physiol 47(1):51–57

    Article  CAS  PubMed  Google Scholar 

  57. Wehrlin JP, Hallen J (2006) Linear decrease in VO2 max and performance with increasing altitude in endurance athletes. Eur J Appl Physiol 96(4):404–412

    Article  PubMed  Google Scholar 

  58. Wen W, Chen X, Huang Z et al (2021) Lycopene increases the proportion of slow-twitch muscle fiber by AMPK signaling to improve muscle anti-fatigue ability. J Nutr Biochem 94:108750

    Article  CAS  PubMed  Google Scholar 

  59. West JB (1990) Limiting factors for exercise at extreme altitudes. Clin Physiol 10(3):265–272

    Article  CAS  PubMed  Google Scholar 

  60. Yadav A, Yadav SS, Singh S et al (2022) Natural products: potential therapeutic agents to prevent skeletal muscle atrophy. Eur J Pharmacol 925:174995

    Article  CAS  PubMed  Google Scholar 

  61. Yeung YG, Stanley ER (2009) A solution for stripping antibodies from polyvinylidene fluoride immunoblots for multiple reprobing. Anal Biochem 389(1):89–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ying F, Zhang L, Bu G et al (2016) Muscle fiber-type conversion in the transgenic pigs with overexpression of PGC1alpha gene in muscle. Biochem Biophys Res Commun 480(4):669–674

    Article  CAS  PubMed  Google Scholar 

  63. Yu T, Dohl J, Park YM et al (2022) Protective effects of dietary curcumin and astaxanthin against heat-induced ROS production and skeletal muscle injury in male and female C57BL/6J mice. Life Sci 288:120160

    Article  CAS  PubMed  Google Scholar 

  64. Zmijewski JW, Banerjee S, Bae H et al (2010) Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J Biol Chem 285(43):33154–33164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zou D, Chen K, Liu P et al (2014) Dihydromyricetin improves physical performance under simulated high altitude. Med Sci Sports Exerc 46(11):2077–2084

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The authors sincerely thank the Director of the Defense Institute of Physiology and Allied Science for providing the necessary resources for conducting the present study. One of the authors, Ms. Asha D Kushwaha, is thankful for obtaining a research fellowship from DRDO.

Author information

Authors and Affiliations

  1. Pathophysiology and Disruptive Technologies, Defense Institute of Physiology and Allied Sciences, Defense Research and Development Organization, Delhi, India, 110054

    Asha D. Kushwaha, Rajeev Varshney & Deepika Saraswat

Authors
  1. Asha D. Kushwaha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rajeev Varshney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Deepika Saraswat
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors participated in the conceptualization and design of the study. ADK experimented and analyzed the data. ADK wrote the manuscript. RV helped during planning and conceptualization of this work. DS has read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Deepika Saraswat.

Ethics declarations

Ethics approval

The Institutional Animal Ethical Committee (IAEC) approved the present research work on animal experiments with reference no. DIPAS/IAEC/2018/10–02, and the experiments were performed following the regulations specified by the IAEC and conformed to the National Guidelines on the Care and Use of Laboratory Animals, India.

Consent for publication

All the authors have read and approved this manuscript and consent for submission.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

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

Key points

1. Hypobaric hypoxia augments the transition of myofibers from slow (oxidative fatigue-resistant) to fast (glycolytic fatigue-susceptible), resulting in a decreased oxidative work capacity.

2. Combinatorial therapy of exercise preconditioning with nanocurcumin formulation (NCF) prevents myofiber transition and thus improves exercise time to exhaustion.

3. NCF administration along with exercise preconditioning also maintains mitochondrial and metabolic homeostasis through PGC1α/SIRT1/AMPK signaling under hypobaric hypoxia condition.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kushwaha, A.D., Varshney, R. & Saraswat, D. Effect of hypobaric hypoxia on the fiber type transition of skeletal muscle: a synergistic therapy of exercise preconditioning with a nanocurcumin formulation. J Physiol Biochem 79, 635–652 (2023). https://doi.org/10.1007/s13105-023-00965-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-023-00965-1

Keywords

Search

Navigation