The Effect of MitoTEMPO on Rat Diaphragm Muscle Contraction Parameters in an Experimental Diabetes Model Induced with Streptozotocin

Ahmet Akkoca; Seçkin Tuncer; Murat Cenk Çelen; Nizamettin Dalkılıç

doi:10.58600/eurjther1912

Authors

Ahmet Akkoca Department of Occupational Health and Safety, Taşkent Vocational School, Selçuk University, Konya, Turkey https://orcid.org/0000-0001-8269-9385
Seçkin Tuncer Department of Biophysics, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey https://orcid.org/0000-0002-7157-0719
Murat Cenk Çelen Department of Biophysics, Faculty of Medicine, Ankara Medipol University, Ankara, Turkey https://orcid.org/0000-0003-0727-0110
Nizamettin Dalkılıç Department of Biophysics, Faculty of Medicine, Başkent University, Ankara, Turkey https://orcid.org/0000-0002-2306-4467

DOI:

https://doi.org/10.58600/eurjther1912

Keywords:

Diaphragm muscle, Isometric contraction, MitoTEMPO, Diabetes Mellitus

Abstract

Objective: Diabetes Mellitus (DM) not only causes hyperglycemia but also leads to clinical challenges involving respiratory functional impairments. The contraction of the diaphragm reduces pleural pressure, thereby contributing significantly to the process of breathing. This study examines the functional impairments in diaphragm muscle isometric contraction parameters due to increased reactive oxygen species (ROS) associated with DM, as well as the effects of MitoTEMPO, a mitochondria-specific antioxidant, on these impairments.

Methods: Wistar Albino male rats at 12-14 weeks of age were randomly divided into three groups: the control group (CON, n=6), the diabetes group (DM, n=6), and the diabetes + MitoTEMPO (MT, n=6) group. A single dose of 50 mg/kg streptozotocin (STZ) was administered to the rats in the DM and MT groups. When the rats in the MT group reached a blood glucose level of 300 mg/dl, they were administered MitoTEMPO at a dose of 0.7 mg/kg/day for 28 days. Isometric contraction recordings were obtained from diaphragm muscle preparations isolated from the experimental animals at the end of the 28-day period.

Results: Although the effectiveness of mitochondria-specific antioxidants in reducing blood glucose levels in DM is debated in the literature, results for the MT group were interestingly indicative of a statistically significant decrease in blood glucose levels following MitoTEMPO administration at the end of the fourth week. Furthermore, MitoTEMPO exhibited therapeutic effects on diaphragm muscle contraction parameters impaired by DM.

Conclusion: The findings suggest that in DM patients, MitoTEMPO could be utilized for blood glucose control and might also be effective in the treatment of DM-induced diaphragm muscle mechanical dysfunction.

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References

Barman S, Srinivasan K (2022) Diabetes and zinc dyshomeostasis: Can zinc supplementation mitigate diabetic complications?. Crit Rev Food Sci Nutr 62(4):1046–1061. https://doi.org/10.1080/10408398.2020.1833178

Lovic D, Piperidou A, Zografou I, Grassos H, Pittaras A, Manolis A (2020) The Growing Epidemic of Diabetes Mellitus. Curr Vasc Pharmacol 18(2):104–109. https://doi.org/10.2174/1570161117666190405165911

Bigagli E, Lodovici M (2019) Circulating Oxidative Stress Biomarkers in Clinical Studies on Type 2 Diabetes and Its Complications.Oxid Med Cell Logev 2019:5953685. https://doi.org/10.1155/2019/5953685

Turkmen K (2017) Inflammation, oxidative stress, apoptosis, and autophagy in diabetes mellitus and diabetic kidney disease: the Four Horsemen of the Apocalypse. Int Urol Nephrol 49(5):837–844. https://doi.org/10.1007/s11255-016-1488-4

Darenskaya MA, Kolesnikova LI, Kolesnikov SI (2021) Oxidative Stress: Pathogenetic Role in Diabetes Mellitus and Its Complications and Therapeutic Approaches to Correction. Bull Exp Biol Med 171(2):179–189. https://doi.org/10.1007/s10517-021-05191-7

Smith RA, Murphy MP (2011) Mitochondria-targeted antioxidants as therapies. Discov Med 11(57):106–114. https://doi.org/10.1002/cbf.1737

Battogtokh G, Choi YS, Kang DS, Park SJ, Shim MS, Huh KM, Cho YY, Lee JY, Lee HS, Kang HC (2018) Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives. Acta Pharm Sin B 8(6):862–880. https://doi.org/10.1016/j.apsb.2018.05.006

Apostolova N, Victor VM (2015) Molecular strategies for targeting antioxidants to mitochondria: therapeutic implications. Antioxid Redox Signal 2015;22(8):686-729. https://doi.org/10.1089/ars.2014.5952

Tuncer S, Dalkilic N, Burat I (2017) Electrophysiological alterations in diaphragm muscle caused by abdominal ischemia-reperfusion. Respir Physiol Neurobiol 238:7-13. https://doi.org/10.1016/j.resp.2016.12.015

Su LJ, Zhang JH, Gomez H, Murugan R, Hong X, Xu D, Jiang F, Peng ZY (2019) Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis. Oxid Med Cell Longev 2019:5080843. https://doi.org/10.1155/2019/5080843

Ford W, Self WH, Slovis C, McNaughton CD (2013) Diabetes in the Emergency Department and Hospital: Acute Care of Diabetes Patients. Curr Emerg Hosp Med Rep 1(1):1-9. https://doi.org/10.1007/s40138-012-0007-x

Akkoca A, Büyükakıllı B, Ballı E, Gültekin B, Özbay E, Oruç Demirbağ H, Türkseven ÇH (2023) Protective effect of MitoTEMPO against cardiac dysfunction caused by ischemia-reperfusion: MCAO stroke model study. Int J Neurosci 1–12. https://doi.org/10.1080/00207454.2023.2273768

Akkoca A, Celen MC, Tuncer S, Dalkilic N (2022) Abdominal Ischemia-Reperfusion Induced Cardiac Dysfunction Can Be Prevented by MitoTEMPO. J Invest Surg 35(3):577-583. https://doi.org/10.1080/08941939.2021.1902593

Uhl S, Freichel M, Mathar I (2015) Contractility Measurements on Isolated Papillary Muscles for the Investigation of Cardiac Inotropy in Mice. J Vis Exp (103):53076. Published 2015 Sep 17. https://doi.org/10.3791/53076

Ravens U, Link S, Gath J, Noble MI (1995) Post-rest potentiation and its decay after inotropic interventions in isolated rat heart muscle. Pharmacol Toxicol 76(1):9–16. https://doi.org/10.1111/j.1600-0773.1995.tb00095.x

Espino-Gonzalez E, Tickle PG, Benson AP, Kissane RWP, Askew GN, Egginton S, Bowen TS (2021) Abnormal skeletal muscle blood flow, contractile mechanics and fibre morphology in a rat model of obese-HFpEF. J Physiol 599(3):981–1001. https://doi.org/10.1113/JP280899

Visca D, Pignatti P, Spanevello A, Lucini E, La Rocca E (2018) Relationship between diabetes and respiratory diseases-Clinical and therapeutic aspects. Pharmacol Res 137:230-235. https://doi.org/10.1016/j.phrs.2018.10.008

Tuncer S, Akkoca A, Celen MC, Dalkilic N (2021) Can MitoTEMPO protect rat sciatic nerve against ischemia-reperfusion injury?. Naunyn Schmiedebergs Arch Pharmacol 394(3):545-553. https://doi.org/10.1007/s00210-020-02039-1

Kabitz HJ, Sonntag F, Walker D, Schwoerer A, Walterspacher S, Kaufmann S, Beuschlein F, Seufert J, Windisch W (2008) Diabetic polyneuropathy is associated with respiratory muscle impairment in type 2 diabetes. Diabetologia 51(1):191–197. https://doi.org/10.1007/s00125-007-0856-0

Hegde SV, Adhikari P, Subbalakshmi NK, Nandini M, Rao GM, D'Souza V (2012) Diaphragmatic breathing exercise as a therapeutic intervention for control of oxidative stress in type 2 diabetes mellitus. Complement Ther Clin Pract 18(3):151-153. https://doi.org/10.1016/j.ctcp.2012.04.002

Mason SA, Wadley GD, Keske MA, Parker L (2022) Effect of mitochondrial-targeted antioxidants on glycaemic control, cardiovascular health, and oxidative stress in humans: A systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab 24(6):1047-1060. https://doi.org/10.1111/dom.14669

Jeong EM, Chung J, Liu H, Go Y, Gladstein S, Farzaneh-Far A, Lewandowski ED, Dudley SC Jr (2016). Role of Mitochondrial Oxidative Stress in Glucose Tolerance, Insulin Resistance, and Cardiac Diastolic Dysfunction. J Am Heart Assoc 5(5):e003046. https://doi.org/10.1161/JAHA.115.003046

Virgana R, Atik N, Gunadi JW, Jonathan E, Ramadhani DE, Soetadji RS, Goenawan H, Lesmana R, Kartasasmita A (2022). MitoTEMPOL Inhibits ROS-Induced Retinal Vascularization Pattern by Modulating Autophagy and Apoptosis in Rat-Injected Streptozotocin Model. Life (Basel) 12(7):1-12. https://doi.org/10.3390/life12071061

Xiao L, Xu X, Zhang F, Wang M, Xu Y, Tang D, Wang J, Qin Y, Liu Y, Tang C, He L, Greka A, Zhou Z, Liu F, Dong Z, Sun L (2017) The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1. Redox biology, 11:297–311. https://doi.org/10.1016/j.redox.2016.12.022

Plecitá-Hlavatá L, Engstová H, Ježek J, Holendová B, Tauber J, Petrásková L, Křen V, Ježek P (2019) Potential of Mitochondria-Targeted Antioxidants to Prevent Oxidative Stress in Pancreatic β-cells. Oxid Med Cell Longev 2019:1826303. https://doi.org/10.1155/2019/1826303

Lin L, Chen Z, Huang C, Wu Y, Huang L, Wang L, Ke S, Liu L (2023) Mito-TEMPO, a Mitochondria-Targeted Antioxidant, Improves Cognitive Dysfunction due to Hypoglycemia: an Association with Reduced Pericyte Loss and Blood-Brain Barrier Leakage. Mol Neurobiol 60(2):672–686. https://doi.org/10.1007/s12035-022-03101-0

Xing H, Zhang Z, Shi G, He Y, Song Y, Liu Y, Harrington EO, Sellke FW, Feng J (2021) Chronic Inhibition of mROS Protects Against Coronary Endothelial Dysfunction in Mice With Diabetes. Front Cell Dev Biol 9:643810. https://doi.org/10.3389/fcell.2021.643810

Brotto M, Brotto L, Jin JP, Nosek TM, Romani A (2010) Temporal adaptive changes in contractility and fatigability of diaphragm muscles from streptozotocin-diabetic rats. J Biomed Biotechnol 2010:931903. https://doi.org/10.1155/2010/931903

De Jong A, Carreira S, Na N, Carillion A, Jiang C, Beuvin M, Lacorte JM, Bonnefont-Rousselot D, Riou B, Coirault C (2017) Diaphragmatic function is enhanced in fatty and diabetic fatty rats. PloS one 12(3):e0174043. https://doi.org/10.1371/journal.pone.0174043

RodríGuez-Reyes N, RodríGuez-Zayas AE, Javadov S, Frontera WR (2016) Single muscle fiber contractile properties in diabetic RAT muscle. Muscle Nerve 53(6):958-964. https://doi.org/10.1002/mus.24988

Lamberts RR, Lingam SJ, Wang HY, Bollen IA, Hughes G, Galvin, IF, Bunton RW, Bahn A, Katare R, Baldi JC, Williams MJ, Saxena P, Coffey S, Jones PP (2014) Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction. Cardiovasc Diabetol 13(72):1-12. https://doi.org/10.1186/1475-2840-13-72

Peixoto JVC, Santos ASR Jr, Corso CR, da Silva FS, Capote A, Ribeiro CD, Abreu BJDGA, Acco A, Fogaça RH, Dias FAL (2020) Thirty-day experimental diabetes impairs contractility and increases fatigue resistance in rat diaphragm muscle associated with increased anti-oxidative activity. Can J Physiol Pharmacol 98(8):490–497. https://doi.org/10.1139/cjpp-2019-0609

Munusamy S, Saba H, Mitchell T, Megyesi JK, Brock RW, Macmillan-Crow LA (2009) Alteration of renal respiratory Complex-III during experimental type-1 diabetes. BMC Endocr Disord 9(2):1-9. https://doi.org/10.1186/1472-6823-9-2

Rücker B, Abreu-Vieira G, Bischoff LB, Harthmann AD, Sarkis JJ, Wink MR, Casali EA (2010) The nucleotide hydrolysis is altered in blood serum of streptozotocin-induced diabetic rats. Arch Physiol Biochem 116(2):79–87. https://doi.org/10.3109/13813451003777067

Li W, Roy Choudhury G, Winters A, Prah J, Lin W, Liu R, Yang SH (2018) Hyperglycemia Alters Astrocyte Metabolism and Inhibits Astrocyte Proliferation. Aging Dis 9(4):674–684. https://doi.org/10.14336/AD.2017.1208

Laitano O, Ahn B, Patel N, Coblentz PD, Smuder AJ, Yoo JK, Christou DD, Adhihetty PJ, Ferreira LF (2016) Pharmacological targeting of mitochondrial reactive oxygen species counteracts diaphragm weakness in chronic heart failure. J Appl Physiol 120(7):733–742. https://doi.org/10.1152/japplphysiol.00822.2015

Eshima H, Tamura Y, Kakehi S, Kurebayashi N, Murayama T, Nakamura K, Kakigi R, Okada T, Sakurai T, Kawamori R, Watada H (2017) Long-term, but not short-term high-fat diet induces fiber composition changes and impaired contractile force in mouse fast-twitch skeletal muscle. Physiol Rep 5(7):e13250. https://doi.org/10.14814/phy2.13250

Wold LE, Dutta K, Mason MM, Ren J, Cala SE, Schwanke ML, Davidoff AJ (2005) Impaired SERCA function contributes to cardiomyocyte dysfunction in insulin resistant rats. J Mol Cell Cardiol 39(2):297–307. https://doi.org/10.1016/j.yjmcc.2005.03.014

Eshima H, Poole DC, Kano Y (2014) In vivo calcium regulation in diabetic skeletal muscle. Cell Calcium 56(5):381-389. https://doi.org/10.1016/j.ceca.2014.08.008

Bisson A, Bodin A, Fauchier G, Herbert J, Angoulvant D, Ducluzeau PH, Lip GYH, Fauchier L (2021) Sex, age, type of diabetes and incidence of atrial fibrillation in patients with diabetes mellitus: a nationwide analysis. Cardiovasc Diabetol 20(1):1-11. https://doi.org/10.1186/s12933-021-01216-7