Skip to main content

Advertisement

SpringerLink
Log in

The reduced contraction capacity of palatopharyngeal muscle in OSAHS is related to the decreased intra-cellular [Ca2+] mediated by low RyR1 and DHPRα1s expression

  • Sleep Breathing Physiology and Disorders • Original Article
  • Published:
Sleep and Breathing Aims and scope Submit manuscript

Abstract

Purpose

To aim of the study was to explore the possible mechanisms for the decreased contraction capacity of the palatopharyngeal muscle in cases with obstructive sleep apnea hypopnea syndrome (OSAHS).

Methods

Palatopharyngeal muscle specimens from patients with OSAHS were taken as the case group. Palatopharyngeal muscle tissue by surgical removal of oropharyngeal malignant tumors was used as a control cohort. The palatopharyngeal muscle contraction capacity was measured by assessing diaphragm peak-twitching force / cross-sectional area (Pt/CSA), fatigue index (FI) twitch tension, and force per cross-sectional area (Force/CSA). Myofibril and sarcoplasmic reticulum (SR) ultra-structures were observed by electron microscopy. The intra-cellular calcium concentration was measured by fluorescence spectrophotometry. DHPRα1s and RyR1 expression profiles were probed through RT-qPCR and Western blot, and the colocalization of them was determined by immunofluorescence.

Results

In comparison with the control cohort, the OSAHS cohort demonstrated decreased Pt/CSA (P < 0.01), FI twitch tension (P < 0.01), together with contraction capacity (P < 0.01). This cohort also had lower intra-cellular [Ca2+] of palatopharyngeal muscle cells with abnormal ultrastructure of sarcoplasmic reticulum (SR) (P < 0.01). In addition, transcriptomic (P < 0.01) and proteomic expression (P < 0.01) for RyR1 and DHPRα1s were markedly reduced within OSAHS cohort, although the degree of colocalization of them was not altered.

Conclusion

RyR1 and DHPRα1s downregulation may disrupt intra-cellular [Ca2+] homeostasis and subsequently decrease the palatopharyngeal muscle contraction capacity in patients with OSAHS, thus providing a novel insight into the pathogenesis of OSAHS.

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

Similar content being viewed by others

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Abbreviations

BSA:

Bovine serum albumin

CSA:

Cross-sectional area

DHPRa1s:

Dihydropyridine receptors

DMEM:

Dulbecco’s modified Eagle medium

ECC:

Excitation–contraction coupling

EM:

Electron microscopy

FI:

Fatigue index

IF:

Immunofluorescence

L0 :

Length of the muscle produced maximal isometric tension

NMF:

Normal myofibril

NSR:

Normal sarcoplasmic reticulum

OSAHS:

Obstructive sleep apnea hypopnea syndrome

P0 :

Maximal tetanic force

PBS:

Phosphate-buffered saline

Pt:

Peak twitch force

RyR1:

Ryanodine receptor

SER:

Smooth endoplasmic reticulum

SR:

Sarcoplasmic reticulum

Vv :

Volume fraction

References

  1. Lee JJ, Sundar KM (2021) Evaluation and Management of Adults with Obstructive Sleep Apnea Syndrome. Lung 199(2):87–101

    Article  PubMed  Google Scholar 

  2. Mohit A, Shrivastava P (2021) Chand, Molecular determinants of obstructive sleep apnea. Sleep Med 80:105–112

    Article  CAS  PubMed  Google Scholar 

  3. Ko CY, Liu QQ, Su HZ, Zhang HP, Fan JM, Yang JH, Hu AK, Liu YQ, Chou D, Zeng YM (2019) Gut microbiota in obstructive sleep apnea-hypopnea syndrome: disease-related dysbiosis and metabolic comorbidities. Clin Sci (Lond) 133(7):905–917

    Article  CAS  Google Scholar 

  4. Garg RK, Afifi AM, Sanchez R, King TW (2016) Obstructive Sleep Apnea in Adults: The Role of Upper Airway and Facial Skeletal Surgery. Plast Reconstr Surg 138(4):889–898

    Article  CAS  PubMed  Google Scholar 

  5. Zhan X, Li L, Wu C, Chitguppi C, Huntley C, Fang F, Wei Y (2019) Effect of uvulopalatopharyngoplasty (UPPP) on atherosclerosis and cardiac functioning in obstructive sleep apnea patients. Acta Otolaryngol 139(9):793–797

    Article  PubMed  Google Scholar 

  6. Eshima H, Poole DC, Kano Y (2014) In vivo calcium regulation in diabetic skeletal muscle. Cell Calcium 56(5):381–389

    Article  CAS  PubMed  Google Scholar 

  7. Allen DG, Lamb GD, Westerblad H (2008) Impaired calcium release during fatigue. J Appl Physiol (1985) 104(1):296–305

    Article  CAS  Google Scholar 

  8. Luo Y, Rall JA (2006) Regulation of contraction kinetics in skinned skeletal muscle fibers by calcium and troponin C. Arch Biochem Biophys 456(2):119–126

    Article  CAS  PubMed  Google Scholar 

  9. Kushnir A, Wajsberg B, Marks AR (2018) Ryanodine receptor dysfunction in human disorders. Biochim Biophys Acta Mol Cell Res 1865(11 Pt B):1687–1697

    Article  CAS  PubMed  Google Scholar 

  10. Clancy JS, Takeshima H, Hamilton SL, Reid MB (1999) Contractile function is unaltered in diaphragm from mice lacking calcium release channel isoform 3. Am J Physiol 277(4 Pt 2):R1205–R1209

    CAS  PubMed  Google Scholar 

  11. Fill M, Copello JA (2002) Ryanodine receptor calcium release channels. Physiol Rev 82(4):893–922

    Article  CAS  PubMed  Google Scholar 

  12. Ogawa Y, Kurebayashi N, Murayama T (2000) Putative roles of type 3 ryanodine receptor isoforms (RyR3). Trends Cardiovasc Med 10(2):65–70

    Article  CAS  PubMed  Google Scholar 

  13. Dulhunty AF, Wei-LaPierre L, Casarotto MG, Beard NA (2017) Core skeletal muscle ryanodine receptor calcium release complex. Clin Exp Pharmacol Physiol 44(1):3–12

    Article  CAS  PubMed  Google Scholar 

  14. Wang MM, Hao LY, Guo F, Zhong B, Zhong XM, Yuan J, Hao YF, Zhao S, Sun XF, Lei M, Jiao GY (2017) Decreased intracellular [Ca(2+) ] coincides with reduced expression of Dhpralpha1s, RyR1, and diaphragmatic dysfunction in a rat model of sepsis. Muscle Nerve 56(6):1128–1136

    Article  CAS  PubMed  Google Scholar 

  15. Jiao GY, Hao LY, Gao CE, Chen L, Sun XF, Yang HL, Li Y, Dai YN (2013) Reduced DHPRalpha1S and RyR1 expression levels are associated with diaphragm contractile dysfunction during sepsis. Muscle Nerve 48(5):745–751

    Article  CAS  PubMed  Google Scholar 

  16. Du K, Liu M, Zhong X, Yao W, Xiao Q, Wen Q, Yang B, Wei M (2018) Epigallocatechin Gallate Reduces Amyloid beta-Induced Neurotoxicity via Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis. Mol Nutr Food Res 62(8):e1700890

    Article  PubMed  Google Scholar 

  17. Tangel DJ, Mezzanotte WS, White DP (1991) Influence of sleep on tensor palatini EMG and upper airway resistance in normal men. J Appl Physiol (1985) 70(6):2574–81

    Article  CAS  Google Scholar 

  18. Malhotra A, Fogel RB, Edwards JK, Shea SA, White DP (2000) Local mechanisms drive genioglossus activation in obstructive sleep apnea. Am J Respir Crit Care Med 161(5):1746–1749

    Article  CAS  PubMed  Google Scholar 

  19. Dong J, Niu X, Chen X (2020) Injury and Apoptosis in the Palatopharyngeal Muscle in Patients with Obstructive Sleep Apnea-Hypopnea Syndrome. Med Sci Monit 26:e919501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Boyd JH, Petrof BJ, Hamid Q, Fraser R, Kimoff RJ (2004) Upper airway muscle inflammation and denervation changes in obstructive sleep apnea. Am J Respir Crit Care Med 170(5):541–546

    Article  PubMed  Google Scholar 

  21. Friberg D, Ansved T, Borg K, Carlsson-Nordlander B, Larsson H, Svanborg E (1998) Histological indications of a progressive snorers disease in an upper airway muscle. Am J Respir Crit Care Med 157(2):586–593

    Article  CAS  PubMed  Google Scholar 

  22. Series F, Simoneau JA, St Pierre S (2000) Muscle fiber area distribution of musculus uvulae in obstructive sleep apnea and non-apneic snorers. Int J Obes Relat Metab Disord 24(4):410–5

    Article  CAS  PubMed  Google Scholar 

  23. Lynch PJ, Tong J, Lehane M, Mallet A, Giblin L, Heffron JJ, Vaughan P, Zafra G, MacLennan DH, McCarthy TV (1999) A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease. Proc Natl Acad Sci U S A 96(7):4164–4169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Avila G, Dirksen RT (2001) Functional effects of central core disease mutations in the cytoplasmic region of the skeletal muscle ryanodine receptor. J Gen Physiol 118(3):277–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Andersson DC, Meli AC, Reiken S, Betzenhauser MJ, Umanskaya A, Shiomi T, D’Armiento J, Marks AR (2012) Leaky ryanodine receptors in beta-sarcoglycan deficient mice: a potential common defect in muscular dystrophy. Skelet Muscle 2(1):9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bellinger AM, Reiken S, Carlson C, Mongillo M, Liu X, Rothman L, Matecki S, Lacampagne A, Marks AR (2009) Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 15(3):325–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Samso M (2015) 3D Structure of the Dihydropyridine Receptor of Skeletal Muscle. Eur J Transl Myol 25(1):4840

    Article  PubMed  PubMed Central  Google Scholar 

  28. Cheng W, Altafaj X, Ronjat M, Coronado R (2005) Interaction between the dihydropyridine receptor Ca2+ channel beta-subunit and ryanodine receptor type 1 strengthens excitation-contraction coupling. Proc Natl Acad Sci U S A 102(52):19225–19230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. FleuryCurado T, Pho H, Freire C, Amorim MR, Bonaventura J, Kim LJ, Lee R, Cabassa ME, Streeter SR, Branco LG, Sennes LU, Fishbein K, Spencer RG, Schwartz AR, Brennick MJ, Michaelides M, Fuller DD, Polotsky VY (2021) Designer Receptors Exclusively Activated by Designer Drugs Approach to Treatment of Sleep-disordered Breathing. Am J Respir Crit Care Med 203(1):102–110

    Article  Google Scholar 

  30. Perger E, Taranto-Montemurro L (2021) Upper airway muscles: influence on obstructive sleep apnoea pathophysiology and pharmacological and technical treatment options. Curr Opin Pulm Med 27(6):505–513

    Article  PubMed  Google Scholar 

Download references

Funding

This study was supported by Youth backbone support Program of China Medical University (QGJ2018061).

Author information

Author notes

  1. Mengmeng Wang, Qian Zhao, and Zitai Ma contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, China Medical University, No. 77 of Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China

    Mengmeng Wang, Qian Zhao, Zitai Ma & Ke Du

  2. Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, 110122, Liaoning, China

    Mengmeng Wang & Huaian Yang

  3. Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, No. 77 of Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China

    Liying Hao

Authors
  1. Mengmeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zitai Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huaian Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liying Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ke Du
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KD, LH and MW conceived and designed the experiments. MW, QZ, ZT M and HY performed the examination and prepared Figures. KD and LH wrote the manuscript; KD, LH and MW reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Liying Hao or Ke Du.

Ethics declarations

Conflicts of interest

None of the authors has any conflict of interest to disclose.

Ethics approval and consent to participate

Ethical approval was obtained from the ethics committee of Shengjing Hospital of China Medical University (2020PS363K(X1)) and informed consent obtained from all participants.

Consent for publication

Not applicable.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, M., Zhao, Q., Ma, Z. et al. The reduced contraction capacity of palatopharyngeal muscle in OSAHS is related to the decreased intra-cellular [Ca2+] mediated by low RyR1 and DHPRα1s expression. Sleep Breath 26, 1791–1799 (2022). https://doi.org/10.1007/s11325-022-02562-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11325-022-02562-w

Keywords

Search

Navigation