The myoprotective effect of non-quantal acetylcholine: in vitro model of the myopathy component of chronic inflammatory demyelinating polyneuropathy

Cover Page

Cite item

Full Text

Abstract

Introduction. Chronic inflammatory demyelinating polyneuropathy (CIDP) is one of the most common primary polyneuropathies. A degenerative process is the underlying cause of muscular atrophy in CIDP, while muscle strength may not fully recover in patients after pathogenesis-based treatment, thus extending the period of disability. Information about factors affecting the trophic function of muscles can be used to treat neuromuscular disorders.

Study aim — to examine the trophotropic properties of the study participants' blood plasma and the myoprotective effect of acetylcholine concentration equivalent to non-quantal release, using an in vitro model of the myopathy component of CIDP.

Materials and methods. The study included 25 patients diagnosed with typical CIDP in accordance with the EFNS/PNS 2010 criteria. The control group consisted of 25 healthy individuals. Serum antibody levels to the nicotinic acetylcholine receptor were measured in all study participants. A method for organotypic cultivation of skeletal muscle tissue and an in vitro model of the myopathy component of CIPD were developed. The effect of the study participants' blood plasma on the growth of skeletal muscle explants in organotypic culture was assessed.

Results. Patients with CIPD were found to have symmetrical sensorimotor polyneuropathy of varying severity (100%); muscle atrophy (88%), and sensory ataxia (84%). The median INCAT Overall Disability Sum Score was 2 [1; 3] for the arms and 3 [2; 5] for the legs. The median Neurological Impairment Scale (NIS) score was 17 [10; 34]. The nicotinic acetylcholine receptor antibody levels were higher in patients with CIDP (0.47 [0.31; 0.54] nmol/l) than in the control group (0.02 [0.01; 0.03] nmol/l). For the first time, a myotoxic effect of the blood plasma from patients with CIDP was observed in organotypic skeletal muscle culture. Using 1:70 and 1:100 dilutions, patient blood plasma inhibited the growth of explants by 27% (n = 120; p < 0.001) and 21% (n = 120; p < 0.001), respectively. This myotoxic effect removed acetylcholine at a concentration equivalent to non-quantal release (10–8 М).

Conclusion. These results expand our understanding of skeletal muscle damage in CIPD and the role of non-quantal acetylcholine in regulating skeletal muscle growth.

About the authors

Arthur V. Gavrichenko

First Saint Petersburg State Medical University; Pavlov Institute of Physiology

Author for correspondence.
Email: arthyrgavrichenko@gmail.com
ORCID iD: 0000-0002-1286-7192

neurologist

Russian Federation, St. Petersburg; St. Petersburg

Natalia A. Pasatetckaia

First Saint Petersburg State Medical University; Almazov National Medical Research Centre

Email: 79046449523@yandex.ru
ORCID iD: 0000-0001-8979-6460

Cand. Sci. (Biol.), Associate Professor, Department of normal physiology, junior researcher

Russian Federation, St. Petersburg; St. Petersburg

Maria G. Sokolova

Herzen State Pedagogical University of Russia

Email: sokolova.m08@mail.ru
ORCID iD: 0000-0002-3829-9971

D. Sci. (Med.), Associate Professor, Department of human and animal anatomy and physiology

Russian Federation, St. Petersburg

Ekaterina V. Lopatina

First Saint Petersburg State Medical University; Pavlov Institute of Physiology

Email: evlopatina@yandex.ru
ORCID iD: 0000-0003-0729-5852

D. Sci. (Biol.), Head, Department of normal physiology, leading researcher, Laboratory of physiology of cardiovascular system and lymphology

Russian Federation, St. Petersburg; St. Petersburg

References

  1. Dyck P.J.B., Tracy J.A. History, Diagnosis, and management of chronic inflammatory demyelinating polyradiculoneuropathy. Mayo Clin. Proc. 2018; 93(6): 777–793. doi: 10.1016/j.mayocp.2018.03.026
  2. Gilmore K.J., Kirk E.A., Doherty T.A. Abnormal motor unit firing rates in chronic inflammatory demyelinating polyneuropathy. J. Neurol. Sci. 2020; 414: 116859. doi: 10.1016/j.jns.2020.116859
  3. Hokkoku K., Matsukura K., Uchida Y. Quantitative muscle ultrasound is useful for evaluating secondary axonal degeneration in chronic inflammatory demyelinating polyneuropathy. Brain Behav. 2017; 7(10): e00812. doi: 10.1002/brb3.812
  4. Markvardsen L.K., Carstens A.K.R., Knak K.L. Muscle strength and aerobic capacity in patients with CIDP one year after participation in an exercise trial. J. Neuromuscul. Dis. 2019; 6(1): 93–97. doi: 10.3233/JND-180344
  5. Gilmore K.J., Fanous J., Doherty T.J. Nerve dysfunction leads to muscle morphological abnormalities in chronic inflammatory demyelinating polyneuropathy assessed by MRI. Clin. Anat. 2020; 33(1): 77–84. doi: 10.1002/ca.23473
  6. Mitchell J.F., Silver A. The spontaneous release of acetylcholine from the denervated hemidiaphragm of the rat. J. Physiol. 1963; 165(1): 117–129. doi: 10.1113/jphysiol.1963.sp007046
  7. Кубасов И.В., Кривой И.И., Лопатина Е.В. Влияние экзогенного ацетилхолина на нервно-мышечную передачу утомляемой диафрагмы крысы. Бюллетень экспериментальной биологии и медицины. 1994; 118 (5): 1153–1155. Kubasov I.V., Krivoj I.I., Lopatina E.V. The effect of exogenous acetylcholine on the neuromuscular transmission of the fatigued rat diaphragm. Bull. Exp. Biol. Med. 1994; 118 (5): 1153–1155. (In Russ.)
  8. Кривой И.И., Кубасов И.В., Лопатина Е.В. Исследование восстановления работоспособности утомляемой диафрагмы крысы после применения экзогенного ацетилхолина. Физиологический журнал им. И.М. Сеченова. 1994; 80(9): 61–66. Krivoj I.I., Kubasov I.V., Lopatina E.V. Investigation of the restoration of the working capacity of the fatigued rat diaphragm after the use of exogenous acetylcholine. Fiziologicheskiy zhurnal im. I.M. Sechenova. 1994; 80(9): 61–66. (In Russ.)
  9. Кривой И.И., Кравцова В.В., Лопатина Е.В. Гиперполяризующий эффект ацетилхолина в скелетной мышце с различным типом мышечных волокон. Журнал эволюционной биохимии и физиологии. 2000; 36(24): 377–379. Krivoj I.I., Kravsova V.V., Lopatina E.V. Hyperpolarizing effect of acetylcholine in skeletal muscle with different types of muscle fibers. Zhurnal evolyutsionnoy biokhimii i fiziologii. 2000; 36(24): 377–379. (In Russ.)
  10. Cisterna B.A., Vargas A.A., Puebla C. Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation. Nat. Commun. 2020; 11(1): 1073. doi: 10.1038/s41467-019-14063-8
  11. Van den Bergh P.Y.K., Hadden R.D.M., Bouche P., Cornblath D.R. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society — first revision. Eur. J. Neurol. 2010; 17(3): 356–363. doi: 10.1111/j.1468-1331.2009.02930.x
  12. Супонева Н.А., Наумова Е.С., Гнедовская Е.В. Хроническая воспалительная демиелинизирующая полинейропатия у взрослых: принципы диагностики и терапия первой линии. Нервно-мышечные болезни. 2016; 6(1): 44–53. Suponeva N.A., Naumova E.S., Gnedovskaya E.V. Chronic inflammatory demyelinating polyneuropathy in adults: diagnostic approaches and first line therapy. Nervno-myshechnye bolezni. 2016; 6(1): 44–53. (In Russ.) DOI: 10.17 650/2222-8721-2016-6-1-44-53
  13. Dolly J.O., Barnard E.A. Nicotinic acetylcholine receptors: An overview. Biochem Pharmacol. 1984; 33(6): 841–858. doi: 10.1016/0006-2952(84)90437-4
  14. Lindstrom J., Criado M., Ratnam M. Using monoclonal antibodies to determine the structures of acetylcholine receptors from electric organs, muscles, and neurons. Ann. N. Y. Acad. Sci. 1987; 505: 208–225. doi: 10.1111/j.1749-6632.1987.t
  15. Sudhof T.S. The synaptic vesicle cycle. Annu. Rev. Neurosci. 2004; 27: 509–547. doi: 10.1146/annurev.neuro.26.041002.131412
  16. Kuffler S.W., Yoshikami D. The number of transmitter molecules in a quantum: an estimate from iontophoretic application of acetylcholine at the neuromuscular synapse. J. Physiol. 1975; 251(2): 465–482. doi: 10.1113/jphysiol.1975.sp011103
  17. Fletcher P., Forrester T. The effect of curare on the release of acetylcholine from mammalian motor nerve terminals and an estimate of quantum content. J. Physiol. 1975; 251(1): 131–144. doi: 10.1113/jphysiol.1975.sp011084
  18. Nikolsky E.E., Oranska T.I., Vyskocil F. Non-quantal acetylcholine release in the mouse diaphragm after phrenic nerve crush and during recovery. Exp. Physiol. 1996; 81(3): 341–348. doi: 10.1113/expphysiol.1996.sp003938
  19. Vyskocil F., Vrbova G. Non-quantal release of acetylcholine affects polyneuronal innervation on developing rat muscle fibres. Eur. J. Neurosci. 1993; 5(12): 1677–1683. doi: 10.1111/j.1460-9568.1993.tb00235.x
  20. Bray J.J., Forrest J.W., Hubbard J.I. Evidence for the role of non-quantal acetylcholine in the maintenance of the membrane potential of rat skeletal muscle. J. Physiol. 1982; 326: 285–296. doi: 10.1113/jphysiol.1982.sp014192

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. The effect of blood plasma of patients with CIDP on the growth of skeletal muscle explants. *p<0.001 compared with the control group.

Download (86KB)
Indexing metadata
3. Fig. 2. Acetylcholine concentration equivalent to non-quantal release (10–8 М) offsets the mytotoxic effect of the blood plasma of patients with CIPD. *p < 0.001 compared with the control group.

Download (55KB)
Indexing metadata

Copyright (c) 2022 Gavrichenko A.V., Pasatetckaia N.A., Sokolova M.G., Lopatina E.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies