Cycling Exercise Training Enhances Platelet Mitochondrial Bioenergetics in Patients with Peripheral Arterial Disease: A Randomized Controlled Trial

Abstract

Exercise training influences the risk of vascular thrombosis in patients with peripheral arterial disease (PAD). Mitochondrial functionalities in platelets involve the cellular bioenergetics and thrombogenesis. This study aimed to elucidate the effect of cycling exercise training (CET) on platelet mitochondrial bioenergetics in PAD patients. Forty randomly selected patients with PAD engaged in general rehabilitation (GR) with CET (i.e., cycling exercise at ventilation threshold for 30 minute/day, 3 days/week) (GR + CET, n = 20) or to a control group that only received GR course (n = 20) for 12 weeks. Systemic aerobic capacity and platelet mitochondrial bioenergetics that included oxidative phosphorylation (OXPHOS) and electron transport system (ETS) were measured using automatic gas analysis and high-resolution respirometry, respectively. The experimental results demonstrated that GR + CET for 12 weeks significantly (1) elevated VO_2peak and lowered V_E-VCO₂ slope, (2) raised resting ankle-brachial index and enhanced cardiac output response to exercise, (3) increased the distance in 6-minute walk test and raised the Short Form-36 physical/mental component scores, and (4) enhanced capacities of mitochondrial OXPHOS and ETS in platelets by activating FADH2 (complex II)-dependent pathway. Moreover, changes in VO_2peak levels were positively associated with changes in platelet OXPHOS and ETS capacities. However, no significant changes in systemic aerobic capacity, platelet mitochondrial bioenergetics, and health-related quality of life (HRQoL) occurred following GR alone. Hence, we conclude that CET effectively increases the capacities of platelet mitochondrial bioenergetics by enhancing complex II activity in patients with PAD. Moreover, the exercise regimen also enhanced functional exercise capacity, consequently improving HRQoL in PAD patients.

Keywords

peripheral arterial disease - exercise - platelet - mitochondria

Authors' Contributions

J.-S.W., T.-C.F., and C.-C.H. were involved in conception and design of research; M.-L.L., T.-C.F., S.-C.H., and Y.-T.L. performed experiments; J.-S.W., T.-C.F., and M.-L.L. analyzed data, interpreted results of experiments, prepared the figures, and drafted the paper; J.-S.W. and T.-C.F. edited and revised the paper; J.-S.W., M.-L.L., T.-C.F., C.-C.H., S.-C.H., and Y.-T.L. approved the final version of the paper.

^* Equal contribution as the first author.

Publication History

Received: 05 August 2020

Accepted: 17 November 2020

Article published online:
09 January 2021

• References

• 1 Kithcart AP, Beckman JA. ACC/AHA versus ESC guidelines for diagnosis and management of peripheral artery disease: JACC Guideline Comparison. J Am Coll Cardiol 2018; 72 (22) 2789-2801
• 2 Treat-Jacobson D, McDermott MM, Bronas UG. et al; American Heart Association Council on Peripheral Vascular Disease, Council on Quality of Care and Outcomes Research, Council on Cardiovascular and Stroke Nursing. Optimal exercise programs for patients with peripheral artery disease: a scientific statement from the American Heart Association. Circulation 2019; 139 (04) e10-e33
• 3 Treat-Jacobson D, McDermott MM, Beckman JA. et al; American Heart Association Council on Peripheral Vascular Disease, Council on Cardiovascular and Stroke Nursing, Council on Epidemiology and Prevention, Council on Lifestyle and Cardiometabolic Health. Implementation of supervised exercise therapy for patients with symptomatic peripheral artery disease: a science advisory from the American Heart Association. Circulation 2019; 140 (13) e700-e710
• 4 Habib A, Petrucci G, Rocca B. Pathophysiology of thrombosis in peripheral artery disease. Curr Vasc Pharmacol 2020; 18 (03) 204-214
• 5 Zharikov S, Shiva S. Platelet mitochondrial function: from regulation of thrombosis to biomarker of disease. Biochem Soc Trans 2013; 41 (01) 118-123
• 6 Garcia-Souza LF, Oliveira MF. Mitochondria: biological roles in platelet physiology and pathology. Int J Biochem Cell Biol 2014; 50: 156-160
• 7 Akkerman JW. Regulation of carbohydrate metabolism in platelets. A review. Thromb Haemost 1978; 39 (03) 712-724
• 8 Chacko BK, Kramer PA, Ravi S. et al. The Bioenergetic Health Index: a new concept in mitochondrial translational research. Clin Sci (Lond) 2014; 127 (06) 367-373
• 9 Wang JS. Exercise prescription and thrombogenesis. J Biomed Sci 2006; 13 (06) 753-761
• 10 Wang JS, Jen CJ, Kung HC, Lin LJ, Hsiue TR, Chen HI. Different effects of strenuous exercise and moderate exercise on platelet function in men. Circulation 1994; 90 (06) 2877-2885
• 11 Wang JS, Jen CJ, Chen HI. Effects of exercise training and deconditioning on platelet function in men. Arterioscler Thromb Vasc Biol 1995; 15 (10) 1668-1674
• 12 Wang JS, Li YS, Chen JC, Chen YW. Effects of exercise training and deconditioning on platelet aggregation induced by alternating shear stress in men. Arterioscler Thromb Vasc Biol 2005; 25 (02) 454-460
• 13 Wu LH, Chang SC, Fu TC, Huang CH, Wang JS. High-intensity interval training improves mitochondrial function and suppresses thrombin generation in platelets undergoing hypoxic stress. Sci Rep 2017; 7 (01) 4191
• 14 Chou CH, Fu TC, Tsai HH, Hsu CC, Wang CH, Wang JS. High-intensity interval training enhances mitochondrial bioenergetics of platelets in patients with heart failure. Int J Cardiol 2019; 274: 214-220
• 15 Hsu CC, Tsai HH, Fu TC, Wang JS. Exercise training enhances platelet mitochondrial bioenergetics in stroke patients: a randomized controlled trial. J Clin Med 2019; 8 (12) 2186
• 16 Letts JA, Fiedorczuk K, Sazanov LA. The architecture of respiratory supercomplexes. Nature 2016; 537 (7622): 644-648
• 17 Picard M, Taivassalo T, Ritchie D. et al. Mitochondrial structure and function are disrupted by standard isolation methods. PLoS One 2011; 6 (03) e18317
• 18 Pesta D, Gnaiger E. High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol Biol 2012; 810: 25-58
• 19 Misra S, Shishehbor MH, Takahashi EA. et al; American Heart Association Council on Peripheral Vascular Disease, Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing. Perfusion assessment in critical limb ischemia: principles for understanding and the development of evidence and evaluation of devices: a scientific statement from the American Heart Association. Circulation 2019; 140 (12) e657-e672
• 20 Guirguis-Blake JM, Evans CV, Redmond N, Lin JS. Screening for peripheral artery disease using the ankle-brachial index: updated evidence report and systematic review for the US preventive services task force. JAMA 2018; 320 (02) 184-196
• 21 American College of Sports Medicine. General principle of exercise prescription. In: ACSM's Guidelines for Exercise Testing and Prescription. 8th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2009: 152-182
• 22 Arena R, Guazzi M, Myers J. Ventilatory abnormalities during exercise in heart failure: a mini review. Curr Respir Med Rev 2007; 3: 179-187
• 23 ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166 (01) 111-117
• 24 Fu TC, Wang CH, Lin PS. et al. Aerobic interval training improves oxygen uptake efficiency by enhancing cerebral and muscular hemodynamics in patients with heart failure. Int J Cardiol 2013; 167 (01) 41-50
• 25 Sjövall F, Ehinger JK, Marelsson SE. et al. Mitochondrial respiration in human viable platelets--methodology and influence of gender, age and storage. Mitochondrion 2013; 13 (01) 7-14
• 26 Maksimovic M, Vlajinac H, Marinkovic J, Kocev N, Voskresenski T, Radak D. Health-related quality of life among patients with peripheral arterial disease. Angiology 2014; 65 (06) 501-506
• 27 Rontoyanni VG, Nunez Lopez O, Fankhauser GT, Cheema ZF, Rasmussen BB, Porter C. Mitochondrial bioenergetics in the metabolic myopathy accompanying peripheral artery disease. Front Physiol 2017; 8: 141
• 28 Koutakis P, Ismaeel A, Farmer P. et al. Oxidative stress and antioxidant treatment in patients with peripheral artery disease. Physiol Rep 2018; 6 (07) e13650
• 29 Teperman J, Carruthers D, Guo Y. et al. Relationship between neutrophil-lymphocyte ratio and severity of lower extremity peripheral artery disease. Int J Cardiol 2017; 228: 201-204
• 30 Carter HN, Chen CC, Hood DA. Mitochondria, muscle health, and exercise with advancing age. Physiology (Bethesda) 2015; 30 (03) 208-223
• 31 Anzell AR, Maizy R, Przyklenk K, Sanderson TH. Mitochondrial quality control and disease: insights into ischemia-reperfusion injury. Mol Neurobiol 2018; 55 (03) 2547-2564
• 32 Pizzimenti M, Riou M, Charles AL. et al. The rise of mitochondria in peripheral arterial disease physiopathology: experimental and clinical data. J Clin Med 2019; 8 (12) 2125
• 33 Chouchani ET, Pell VR, Gaude E. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014; 515 (7527): 431-435
• 34 Mills E, O'Neill LA. Succinate: a metabolic signal in inflammation. Trends Cell Biol 2014; 24 (05) 313-320
• 35 George JN. Platelets. Lancet 2000; 355 (9214): 1531-1539
• 36 Fu W, Meng G, Yang X, Yu L, Jiang H. Bone marrow sympathetic activation regulates post-myocardial infarction megakaryocyte expansion but not platelet production. Biochem Biophys Res Commun 2019; 513 (01) 99-104
• 37 Wang JS, Cheng LJ. Effect of strenuous, acute exercise on α2-adrenergic agonist-potentiated platelet activation. Arterioscler Thromb Vasc Biol 1999; 19 (06) 1559-1565
• 38 Weng X, Liu H, Zhang X. et al. An α₂-adrenoceptor agonist: dexmedetomidine induces protective cardiomyocyte hypertrophy through mitochondrial-AMPK pathway. Int J Med Sci 2020; 17 (16) 2454-2467