Effect of the large-conductance calcium-dependent k+ channel activator NS1619 on the function of mitochondria in the heart of dystrophin-deficient mice

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Dystrophin-deficient muscular dystrophy (Duchenne dystrophy) is characterized by impaired ion homeostasis, in which mitochondria play an important role. In the present work, using a model of dystrophin-deficient mdx mice, we revealed a decrease in the efficiency of potassium ion transport and the total content of this ion in heart mitochondria. We evaluated the effect of chronic administration of the benzimidazole derivative NS1619, which is an activator of the large-conductance Ca2+-dependent K+ channel (mitoBKCa) on the structure and function of organelles and the state of the heart muscle. It was shown that NS1619 improves K+ transport and increases the content of the ion in the heart mitochondria of mdx mice, but this is not associated with changes in the level of the mitoBKCa protein and the expression of the encoding gene. The effect of NS1619 was accompanied by a decrease in the intensity of oxidative stress, assessed by the level of lipid peroxidation products (MDA products) and normalization of the mitochondrial ultrastructure in the heart of mdx mice. In addition, we found positive changes in the tissue, expressed in a decrease in the level of fibrosis in the heart of dystrophin-deficient animals treated with NS1619. It was noted that NS1619 had no significant effect on the structure and function of heart mitochondria in wild-type animals. The paper discusses the mechanisms of influence of NS1619 on the function of mouse heart mitochondria in Duchenne muscular dystrophy and the prospects for applying this approach to correct pathology.

About the authors

M. V Dubinin

Mari State University

Email: dubinin1989@gmail.com
424001 Yoshkar-Ola, Mari El, Russia

V. S Starinets

Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences

Email: dubinin1989@gmail.com
142290 Pushchino, Moscow Region, Russia

Y. A Chelyadnikova

Mari State University

Email: dubinin1989@gmail.com
424001 Yoshkar-Ola, Mari El, Russia

N. V Belosludtseva

Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences

Email: dubinin1989@gmail.com
142290 Pushchino, Moscow Region, Russia

I. B Mikheeva

Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences

Email: dubinin1989@gmail.com
142290 Pushchino, Moscow Region, Russia

D. K Penkina

Mari State University

Email: dubinin1989@gmail.com
424001 Yoshkar-Ola, Mari El, Russia

A. D Igoshkina

Mari State University

Email: dubinin1989@gmail.com
424001 Yoshkar-Ola, Mari El, Russia

E. Y Talanov

Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences

Email: dubinin1989@gmail.com
142290 Pushchino, Moscow Region, Russia

I. I Kireev

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University

Email: dubinin1989@gmail.com
119991 Moscow, Russia.

References

  1. Emery, A. E. (1991) Population frequencies of inherited neuromuscular diseases - A world survey, Neuromuscul. Disord., 1, 19-29, doi: 10.1016/0960-8966(91)90039-u.
  2. Mavrogeni, S., Markousis-Mavrogenis, G., Papavasiliou, A., and Kolovou, G. (2015) Cardiac involvement in Duchenne and Becker muscular dystrophy, World J. Cardiol., 7, 410-414, doi: 10.4330/wjc.v7.i7.410.
  3. Ignatieva, E., Smolina, N., Kostareva, A., and Dmitrieva, R. (2021) Skeletal muscle mitochondria dysfunction in genetic neuromuscular disorders with cardiac phenotype, Int. J. Mol. Sci., 22, 7349, doi: 10.3390/ijms22147349.
  4. Kamdar, F., and Garry, D. J. (2016) Dystrophin-deficient cardiomyopathy, J. Am. Coll. Cardiol., 67, 2533-2546, doi: 10.1016/j.jacc.2016.02.081.
  5. D'Amario, D., Amodeo, A., Adorisio, R., Tiziano, F. D., Leone, A. M., Perri, G., Bruno, P., Massetti, M., Ferlini, A., Pane, M., Niccoli, G., Porto, I., D'Angelo, G. A., Borovac, J. A., Mercuri, E., and Crea, F. (2017) A current approach to heart failure in Duchenne muscular dystrophy, Heart, 103, 1770-1779, doi: 10.1136/heartjnl-2017-311269.
  6. Ware, S. M. (2017) Genetics of paediatric cardiomyopathies, Curr. Opin. Pediatr., 29, 534-540, doi: 10.1097/MOP.0000000000000533.
  7. Angelini, G., Mura, G., and Messina, G. (2022) Therapeutic approaches to preserve the musculature in Duchenne muscular dystrophy: The importance of the secondary therapies, Exp. Cell Res., 410, 112968, doi: 10.1016/j.yexcr.2021.112968.
  8. Rybalka, E., Timpani, C., Cooke, M. B., Williams, A., and Hayes, A. (2014) Defects in mitochondrial ATP synthesis in dystrophin-deficient mdx skeletal muscles may be caused by complex I insufficiency, PLoS One, 9, e115763, doi: 10.1371/journal.pone.0115763.
  9. Vila, M. C., Rayavarapu, S., Hogarth, M., van der Meulen, J. H., Horn, A., Defour, A., Takeda, S., Brown, K. J., Hathout, Y., Nagaraju, K., and Jaiswal, J. K. (2017) Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy, Cell Death Differ., 24, 330-342, doi: 10.1038/cdd.2016.127.
  10. Schiavone, M., Zulian, A., Menazza, S., Petronilli, V., Argenton, F., Merlini, L., Sabatelli, P., and Bernardi, P. (2017) Alisporivir rescues defective mitochondrial respiration in Duchenne muscular dystrophy, Pharmacol. Res., 125, 122-131, doi: 10.1016/j.phrs.2017.09.001.
  11. Hughes, M. C., Ramos, S. V., Turnbull, P. C., Rebalka, I. A., Cao, A., Monaco, C. M., Varah, N. E., Edgett, B. A., Huber, J. S., Tadi, P., Delfinis, L. J., Schlattner, U., Simpson, J. A., Hawke, T. J., and Perry, C. G. R. (2019) Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H2O2 emission during impaired oxidative phosphorylation, J. Cachexia Sarcopenia Muscle, 10, 643-661, doi: 10.1002/jcsm.12405.
  12. Dubinin, M. V., Talanov, E. Y., Tenkov, K. S., Starinets, V. S., Mikheeva, I. B., Sharapov, M. G., and Belosludtsev, K. N. (2020) Duchenne muscular dystrophy is associated with the inhibition of calcium uniport in mitochondria and an increased sensitivity of the organelles to the calcium-induced permeability transition, Biochim. Biophys. Acta Mol. Basis Dis., 1866, 165674, doi: 10.1016/j.bbadis.2020.165674.
  13. Dubinin, M. V., Talanov, E. Y., Tenkov, K. S., Starinets, V. S., Belosludtseva, N. V., and Belosludtsev, K. N. (2020) The effect of deflazacort treatment on the functioning of skeletal muscle mitochondria in Duchenne muscular dystrophy, Int. J. Mol. Sci., 21, 8763, doi: 10.3390/ijms21228763.
  14. Mareedu, S., Million, E. D., Duan, D., and Babu, G. J. (2021) Abnormal calcium handling in Duchenne muscular dystrophy: mechanisms and potential therapies, Front. Physiol., 12, 647010, doi: 10.3389/fphys.2021.647010.
  15. Zhang, W., ten Hove, M., Schneider, J. E., Stuckey, D. J., Sebag-Montefiore, L., Bia, B. L., Radda, G. K., Davies, K. E., Neubauer, S., and Clarke, K. (2008) Abnormal cardiac morphology, function and energy metabolism in the dystrophic mdx mouse: An MRI and MRS study, J. Mol. Cell. Cardiol., 45, 754-760, doi: 10.1016/j.yjmcc.2008.09.125.
  16. Kyrychenko, V., Poláková, E., Janíček, R., and Shirokova, N. (2015) Mitochondrial dysfunctions during progression of dystrophic cardiomyopathy, Cell Calcium, 58, 186-195, doi: 10.1016/j.ceca.2015.04.006.
  17. Willi, L., Abramovich, I., Fernandez-Garcia, J., Agranovich, B., Shulman, M., Milman, H., Baskin, P., Eisen, B., Michele, D. E., Arad, M., Binah, O., and Gottlieb, E. (2022) Bioenergetic and metabolic impairments in induced pluripotent stem cell-derived cardiomyocytes generated from Duchenne muscular dystrophy patients, Int. J. Mol. Sci., 23, 9808, doi: 10.3390/ijms23179808.
  18. Ascah, A., Khairallah, M., Daussin, F., Bourcier-Lucas, C., Godin, R., Allen, B. G., Petrof, B. J., Rosiers, C. D., Burelle, Y. (2011) Stress-induced opening of the permeability transition pore in the dystrophin-deficient heart is attenuated by acute treatment with sildenafil, Am. J. Physiol. Heart Circ. Physiol., 300, H144-H153, doi: 10.1152/ajpheart.00522.2010.
  19. Dubinin, M. V., Talanov, E. Y., Tenkov, K. S., Starinets, V. S., Mikheeva, I. B., and Belosludtsev, K. N. (2020) Transport of Ca2+ and Ca2+-dependent permeability transition in heart mitochondria in the early stages of Duchenne muscular dystrophy, Biochim. Biophys. Acta Bioenerg., 1861, 148250, doi: 10.1016/j.bbabio.2020.148250.
  20. Angebault, C., Panel, M., Lacôte, M., Rieusset, J., Lacampagne, A., and Fauconnier, J. (2021) Metformin reverses the enhanced myocardial SR/ER-mitochondria interaction and impaired complex I-driven respiration in dystrophin-deficient mice, Front. Cell Dev. Biol., 8, 609493, doi: 10.3389/fcell.2020.609493.
  21. Dubinin, M. V., Starinets, V. S., Talanov, E. Y., Mikheeva, I. B., Belosludtseva, N. V., Serov, D. A., Tenkov, K. S., Belosludtseva, E. V., and Belosludtsev, K. N. (2021) Effect of the non-immunosuppressive MPT pore inhibitor alisporivir on the functioning of heart mitochondria in dystrophin-deficient mdx mice, Biomedicines, 9, 1232, doi: 10.3390/biomedicines9091232.
  22. Bienengraeber, M., Olson, T. M., Selivanov, V. A., Kathmann, E. C., O'Cochlain, F., Gao, F., Karger, A. B., Ballew, J. D., Hodgson, D. M., Zingman, L. V., Pang, Y. P., Alekseev, A. E., and Terzic, A. (2004) ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating, Nat. Genet., 36, 382-387, doi: 10.1038/ng1329.
  23. Farid, T. A., Nair, K., Massé, S., Azam, M. A., Maguy, A., Lai, R. F., Umapathy, K., Dorian, P., Chauhan, V., Varró, A., Al-Hesayen, A., Waxman, M., Nattel, S., and Nanthakumar, K. (2011) Role of KATP channels in the maintenance of ventricular fibrillation in cardiomyopathic human hearts, Circ. Res., 109, 1309-1318, doi: 10.1161/CIRCRESAHA.110.232918.
  24. Graciotti, L., Becker, J., Granata, A. L., Procopio, A. D., Tessarollo, L., and Fulgenzi, G. (2011) Dystrophin is required for the normal function of the cardio-protective K(ATP) channel in cardiomyocytes, PLoS One, 6, e27034, doi: 10.1371/journal.pone.0027034.
  25. Dubinin, M. V., Starinets, V. S., Belosludtseva, N. V., Mikheeva, I. B., Chelyadnikova, Y. A., Penkina, D. K., Vedernikov, A. A., and Belosludtsev, K. N. (2022) The effect of uridine on the state of skeletal muscles and the functioning of mitochondria in Duchenne dystrophy, Int. J. Mol. Sci., 23, 10660, doi: 10.3390/ijms231810660.
  26. Dubinin, M. V., Starinets, V. S., Belosludtseva, N. V., Mikheeva, I. B., Chelyadnikova, Y. A., Igoshkina, A. D., Vafina, A. B., Vedernikov, A. A., and Belosludtsev, K. N. (2022) BKCa activator NS1619 improves the structure and function of skeletal muscle mitochondria in Duchenne dystrophy, Pharmaceutics, 14, 2336, doi: 10.3390/ijms231810660.
  27. Checchetto, V., Leanza, L., De Stefani, D., Rizzuto, R., Gulbins, E., and Szabo, I. (2021) Mitochondrial K+ channels and their implications for disease mechanisms, Pharmacol. Ther., 227, 107874, doi: 10.1016/j.pharmthera.2021.107874.
  28. Zorov, D. B. (2022) A window to the potassium world. The evidence of potassium energetics in the mitochondria and identity of the mitochondrial ATP-dependent K+ channel, Biochemistry (Moscow), 87, 683-688, doi: 10.1134/S0006297922080016.
  29. Juhaszova, M., Kobrinsky, E., Zorov, D. B., Nuss, H. B., Yaniv, Y., Fishbein, K. W., de Cabo, R., Montoliu, L., Gabelli, S. B., Aon, M. A., Cortassa, S., and Sollott, S. J. (2021) ATP Synthase K+- and H+-fluxes drive ATP synthesis and enable mitochondrial K+-"Uniporter" function: I. Characterization of ion fluxes, Function (Oxf), 3, zqab065, doi: 10.1093/function/zqab065.
  30. Juhaszova, M., Kobrinsky, E., Zorov, D. B., Nuss, H. B., Yaniv, Y., Fishbein, K. W., de Cabo, R., Montoliu, L., Gabelli, S. B., Aon, M. A., Cortassa, S., and Sollott, S. J. (2022) ATP synthase K+- and H+-fluxes drive ATP synthesis and enable mitochondrial K+-"Uniporter" function: II. Ion and ATP synthase flux regulation, Function (Oxf), 3, zqac001, doi: 10.1093/function/zqac001.
  31. González-Sanabria, N., Echeverría, F., Segura, I., Alvarado-Sánchez, R., and Latorre, R. (2021) BK in double-membrane organelles: A biophysical, pharmacological, and functional survey, Front. Physiol., 12, 761474, doi: 10.3389/fphys.2021.761474.
  32. Wang, X., Yin, C., Xi, L., and Kukreja, R. C. (2004) Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice, Am. J. Physiol. Heart Circ. Physiol., 287, H2070-H2077, doi: 10.1152/ajpheart.00431.2004.
  33. Lam, J., Katti, P., Biete, M., Mungai, M., AshShareef, S., Neikirk, K., Garza Lopez, E., Vue, Z., Christensen, T. A., Beasley, H. K., Rodman, T. A., Murray, S. A., Salisbury, J. L., Glancy, B., Shao, J., Pereira, R. O., Abel, E. D., and Hinton, A. (2021) A universal approach to analyzing transmission electron microscopy with ImageJ, Cells, 10, 2177, doi: 10.3390/cells10092177.
  34. 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, doi: 10.1006/abio.1976.9999.
  35. Dubinin, M. V., Semenova, A. A., Ilzorkina, A. I., Markelova, N. Y., Penkov, N. V., Shakurova, E. R., Belosludtsev, K. N., and Parfenova, L. V. (2021) New quaternized pyridinium derivatives of betulin: Synthesis and evaluation of membranotropic properties on liposomes, pro- and eukaryotic cells, and isolated mitochondria, Chem. Biol. Interact., 349, 109678, doi: 10.1016/j.cbi.2021.109678.
  36. Belosludtseva, N. V., Starinets, V. S., Pavlik, L. L., Mikheeva, I. B., Dubinin, M. V., and Belosludtsev, K. N. (2020) The effect of S-15176 difumarate salt on ultrastructure and functions of liver mitochondria of C57BL/6 mice with streptozotocin/high-fat diet-induced type 2 diabetes, Biology, 9, 309, doi: 10.3390/biology9100309.
  37. Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S., and Madden, T. L. (2012) Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction, BMC Bioinform., 13, 134, doi: 10.1186/1471-2105-13-134.
  38. Schmittgen, T. D., and Livak, K. J. (2008) Analyzing real-time PCR data by the comparative CT method, Nat. Protoc., 3, 1101-1108, doi: 10.1038/nprot.2008.73.
  39. Quiros, P. M., Goyal, A., Jha, P., and Auwerx, J. (2017) Analysis of mtDNA/nDNA ratio in mice, Curr. Protoc. Mouse Biol., 7, 47-54, doi: 10.1002/cpmo.21.
  40. Szewczyk, A., Skalska, J., Głąb, M., Kulawiak, B., Malińska, D., Koszela-Piotrowska, I., and Kunz, W. S. (2006) Mitochondrial potassium channels: from pharmacology to function, Biochim. Biophys. Acta, 1757, 715-720, doi: 10.1016/j.bbabio.2006.05.002.
  41. Singh, H., Rong, L., Bopassa, J., Meredith, A., Stefani, E., and Toro, L. (2013) MitoBK-Ca is encoded by the KCNMA1 gene, and a splicing sequence defines its mitochondrial location, Proc. Natl. Acad. Sci. USA, 110, 10836-10841, doi: 10.1073/pnas.1302028110.
  42. Heinen, A., Aldakkak, M., Stowe, D. F., Rhodes, S. S., Riess, M. L., Varadarajan, S. G., and Camara, A. K. (2007) Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca2+-sensitive K+ channels, Am. J. Physiol. Heart Circ. Physiol., 293, H1400-H1407, doi: 10.1152/ajpheart.00198.2007.
  43. Kharraz, Y., Guerra, J., Pessina, P., Serrano, A. L., and Muñoz-Cánoves, P. (2014) Understanding the process of fibrosis in Duchenne muscular dystrophy, Biomed. Res. Int., 2014, 965631, doi: 10.1155/2014/965631.
  44. Wissing, E. R., Millay, D. P., Vuagniaux, G., and Molkentin, J. D. (2010) Debio-025 is more effective than prednisone in reducing muscular pathology in mdx mice, Neuromuscul. Disord., 20, 753-760, doi: 10.1016/j.nmd.2010.06.016.
  45. Dubinin, M. V., Starinets, V. S., Talanov, E. Y., Mikheeva, I. B., Belosludtseva, N. V., and Belosludtsev, K. N. (2021) Alisporivir Improves mitochondrial function in skeletal muscle of mdx mice but suppresses mitochondrial dynamics and biogenesis, Int. J. Mol. Sci., 22, 9780, doi: 10.3390/ijms22189780.
  46. Dai, H., Wang, M., Patel, P. N., Kalogeris, T., Liu, Y., Durante, W., and Korthuis, R. J. (2017) Preconditioning with the BKCa channel activator NS-1619 prevents ischemia-reperfusion-induced inflammation and mucosal barrier dysfunction: Roles for ROS and heme oxygenase-1, Am. J. Physiol. Heart Circ. Physiol., 313, H988-H999, doi: 10.1152/ajpheart.00620.2016.
  47. Li, Y., Zhang, S., Zhang, X., Li, J., Ai, X., Zhang, L., Yu, D., Ge, S., Peng, Y., and Chen, X. (2014) Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy, Cardiovasc. Res., 103, 60-71, doi: 10.1093/cvr/cvu119.

Copyright (c) 2023 Russian Academy of Sciences

This website uses cookies

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

About Cookies