تاثیر هشت هفته تمرین مقاومتی در ترکیب با مکمل BCAA نانولیپوزوم بر بیان ژن های HSP60 و HSP70 میتوکندری کاردیومیوسیت های رتهای مدل سکته قلبی
محورهای موضوعی : نقش بیان ژن در سلامتیالهام فرهادفر 1 , ماکان خواجه وندی 2
1 - گروه تربیت بدنی و علوم ورزشی، دانشگاه آزاد اسلامی، واحد دزفول، دزفول
2 - گروه تربیت بدنی و علوم ورزشی، واحد تهران مرکزی، دانشگاه آزاد اسلامی، تهران، ایران
کلید واژه: تمرین مقاومتی, مکمل BCAA نانولیپوزوم, HSP60 و HSP70 و رتهای مدل سکته قلبی.,
چکیده مقاله :
هدف از پژوهش حاضر بررسی تاثیر هشت هفته تمرین مقاومتی در ترکیب با مکمل BCAA نانولیپوزوم بر بیان ژنهای HSP60 و HSP70 میتوکندری کاردیومیوسیتهای رتهای مدل سکته قلبی بود. در اين مطالعه تجربي، 32 سر موش صحرایی نر نژاد ویستار مدل سکته قلبی به صورت تصادفی به 4 گروه کنترل، مکمل (BCAA نانولیپوزوم)، توام (تمرین مقاومتی+ مکمل BCAAنانولیپوزوم) و تمرین (تمرین مقاومتی) تقسیم شدند. تمرين مقاومتي شامل هشت هفته تمرين نردبان با شدت متوسط (70 درصد از MVCC) و پنج روز در هفته بود. در گروه¬های مکمل و توام 5 روز در هفته و به مدت 8 هفته، مکمل BCAA نانولیپوزوم و به میزان 600 میلی گرم به ازای هر کیلوگرم وزن بدن به صورت گاواژ دریافت شد. بیان نسبی ژنهای HSP60 و HSP70 میتوکندری با استفاده از روش Real-time PCR به دست آمد. ﺩﺍﺩﻩ ﻫﺎ ﺑﺎ ﺍﺳﺘﻔﺎﺩ ﺍﺯ ﺁﺯﻣﻮن ﺁﻣﺎری تحلیل واریانس دوطرفه ﻭ ﺁﺯﻣﻮﻥ تعقیبی توکیﺁﻧﺎﻟﻴﺰ ﺷﺪﻧﺪ. كليه عمليات آماري توسط نرم افزار(SPSS) نسخه 23 و سطح معني داري آزمون ها در سطح 05/0≥p مورد تجزیه و تحلیل قرار گرفتند.نتایج آزمون نشان داد که ميانگين بیان ژنهای HSP60 و HSP70 کاردیومیوسیتها در گروههای تمرين کرده با و بدون مصرف BCAA (تمرین+ مکمل و تمرین) به طور معنیداری بیشتر از گروههای تمرين نکرده با و بدون مصرف BCAA (مکمل و کنترل) است. نتایج تحقيق اهميت HSP60 و HSP70 را در تكثير و تمایز سلول های عضلانی همراه با بازسازی از آسيب ناشی از انفارکتوس قلبی را نشان می دهد.
The purpose of this study was to investigate the effect of eight weeks of resistance training in combination with nanoliposome BCAA supplement on the expression of HSP60 and HSP70 genes in mitochondrial cardiomyocytes of heart attack model rats. 32 male Wistar rats with heart attack model were randomly divided into 4 groups: control, supplemented (BCAA nanoliposome), combined (resistance training + BCAA nanoliposome supplement) and training (resistance training). Resistance training consisted of eight weeks of ladder training with moderate intensity (70% of MVCC) and five days a week. In the supplement and combined groups, 5 days a week and for 8 weeks, BCAA nanoliposome supplement was received by gavage in the amount of 600 mg per kilogram of body weight. The relative expression of mitochondrial HSP60 and HSP70 genes was obtained using Real-time PCR method. The data were analyzed using two-way analysis of variance and Tukey's post hoc test. The results of the two-way analysis of variance test showed that the average expression of HSP60 and HSP70 genes in cardiomyocytes in the trained groups with and without BCAA consumption (exercise + supplement and exercise) was significantly higher than the untrained groups with and without consumption. BCAA (supplement and control. The results of this research clearly show the importance of HSP60 and HSP70 in the proliferation and differentiation of muscle cells along with regeneration from damage caused by heart infarction.
1. تامپسون پل. قلب شناسی ورزشی و فعالیت بدنی. ترجمه: دبیدی روشن ولیاله، پوراصغر مهدی، عبدی هدی. انتشارات دانشگاه مازندران. 1389. چاپ اول.
2. سموات طاهره، حجت زاده علی. برنامههای پیشگیری و کنترل بیماریهای قلبی-عروقی. وزارت بهداشت درمان و آموزش پزشکی. معاونت بهداشت. مرکز مدیریت بیماریهای غیرواگیر. اداره قلب و عروق. 1390.
3. قراخانلو رضا، ملانوری مهدیه. نگاهی به سازگاریهای سلولی و مولکولی به تمرینات ورزشی. انتشارات حتمی. 1394. چاپ اول.
4. کبودانیان سوسن، غضنفری طوبی، شاکری راحله. بیوشیمی مرگ سلولی. انتشارات دانشگاه شاهد. 1393. چاپ اول.
5. لودیش هاروی، برک آرنولد، کیسر کریس و همکاران. زیست شناسی سلولی و مولکولی. ترجمه: ستوده نیا عبدالحسین، پروانه لیلا، قربانی محمدحسین، آموزگار افسانه. انتشارات کتاب ارجمند. 1390. چاپ اول.
6. مرکز کنترل و پیشگیری از بیماریها در آمریکا (www.cdc.gov/chronicdisease/overview/index.htm)
7. منتظری فاطمه، رهگذر سهیلا، قائدی کامران. آپوپتوز و ارگانلهای سیتوپلاسمی. ژنتیک در هزاره سوم. 1390. سال نهم، شماره اول، ص:2312-2300.
8. مورن فرانک، ولکر کلوس. فیزیولوژی ورزشی مولکولی و سلولی. ترجمه: ترتیبیان بختیار، اقبالی مهدی، عباسی اصغر، طلوعی آذر جواد، حاجی زاده بهزاد. انتشارات جهاد دانشگاهی. 1391. چاپ اول.
9. Amin H, Vachris J, Hamilton A, Steuerwald N, Howden R, Arthur ST. GSK3β inhibition and LEF1 upregulation in skeletal muscle following a bout of downhill running. J Physiol Sci.2014. 64(1):1-11.
10. Javid Tabrizi N, Bashiri J, Narimani Rad M. [Effect of 12 weeks of treadmill aerobic training on cytochrome C and Caspase-9 gene expression in cardiac muscle of male rats (Persian)]. Qom Univ Med Sci J. 2017; 11(6):1-9.
11. Kwak HB. Effects of aging and exercise training on apoptosis in the heart. J of Exer Rehabi. 2016; 9(2):219-22.
12. Lee Y, Min K, Talbert EE, Kavazis AN, Smuder AJ, Willis WT, et al. Exercise protects cardiac mitochondria against ischemia reperfusion injury. MedSci Sports Exerc. 2018; 44(3):397-405.
13. Phaneuf S, Leeuwenburgh C. Apoptosis and exercise. Med Sci Sports Exerc. 2014; 33(3):393-6.
14. Peterson JM, Bryner RW, Sindler A, Frisbee JC, Alway SE. Mitochondrial apoptotic signaling is elevated in cardiac but not skeletal muscle in the obese Zucker rat and is reduced with aerobic exercise. J Appl Physiol. 2014; 105(6):1934-43.
15. Zhong N, Chen H, Zhao Q, Wang H, Yu X, Eaves AM, et al. Effects of griseofulvin on apoptosis through caspase-3- and caspase-9-dependent pathways in K562 leukemia cells: An in vitro study. Curr Ther Res Clin Exp. 2017; 71(16):384-97.
16. Rodríguez-Berriguete G, Galvis L, Fraile B, de Bethencourt FR, Martínez-Onsurbe P, Olmedilla G, et al. Immunoreactivity to caspase-3, caspase-7, caspase-8, and caspase-9 forms is frequently lost in human prostate tumors. Hum Pathol. 2016; 43(2):229-37.
17. Harada H, Hiraoka M, Kizaka-Kondoh S. Antitumor effect of TAT-oxygendependent degradation-caspase-3 fusion protein specifically stabilized and activated in hypoxic tumor cells. Cancer Res. 2002; 62(7):2013-
18. Javid Tabrizi N, Bashiri J, Narimani Rad M. [Effect of 12 weeks of treadmill aerobic training on cytochrome C and Caspase-9 gene expression in cardiac muscle of male rats (Persian)]. Qom Univ Med Sci J. 2017; 11(6):1-9. http://journal.muq.ac.ir/article-1-869-en.html
19. Siahkohian M, Asgharpour-arshad M, Bolboli L, Jafari A, Sheikhzadeh hesari F. [Effect of 12- weeks aerobic training on some indices of skeletal muscle apoptosis in male rats (Persian)]. Med J Tabriz Univ Med Sci Health Serv. 2018; 39(6):35-43. https://www.sid.ir/fa/journal/ViewPaper.aspx?id=359071
20. Marzetti E, Lawler JM, Hiona A, Manini T, Seo AY, Leeuwenburgh C. Modulation of age-induced apoptotic signaling and cellular remodeling by exercise and calorie restriction in skeletal muscle. Free Radic Biol Med. 2017; 44(2):160-8
21. Lee SD, Shyu WC, Cheng IS, Kuo CH, Chan YS, Lin YM, et al. Effects of exercise training on cardiac apoptosis in obese rats. Nutr Metab Cardiovasc Dis. 2013; 23(6):566-73.
22. Kwak HB, Song W, Lawler JM. Exercise training attenuates ageinduced elevation in Bax/Bcl-2 ratio, apoptosis, and remodeling in the rat heart. FASEB J. 2006; 20(6):791-3.
23. Mernet S, Kayatekin BM, Resmi H, Açıkgöz O, Kaynak C, Özer E. The apoptotic response to strenuous exercise of the gastrocnemius and solues muscle fibers in rats. Eur. J. Appl. Physiol: 2018:102(5), 515-524.
24. Huang Ch, Lin TJ, Chen ChCh, Lin WT. Endurance training accelerates exhaustive exercise-induced mitochondrial DNA deletion and apoptosis of left ventricle myocardium in rats. Eur J Appl Physiol. 2012; 107(6):697. 706.
25. Rastogi RP, Rajeshwar R, Sinha RP. Apoptosis: Molecular mechanisms and pathogenicity. EXCLI J. 2016; 8:155-88.
26. Marzetti E, Privitera G, Simili V, Wohlgemuth SE, Aulisa L, Pahor M, et al. Multiple pathways to the same end: mechanisms of myonuclear apoptosis in sarcopenia of aging. Sci. World J. 2014; 10:340-9
27. Viña J, Gomez-Cabrera MC, Borras C, Froio T, Sanchis-Gomar F, Martinez-Bello VE et al. Mitochondrial biogenesis in exercise and in ageing. Adv Drug Deliv Rev. 2009; 61(14):1369-14.
28. Wang ZB, Liu YQ, Cui YF. Pathways to caspase activation. Cell Biol Int. 2005; 29(7):489-96.
29. Youle RJ, Strasser A. The BCL-2 protein family: Opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2018; 9(1):47-59.[DOI:10.1038/nrm2308] [PMID]
30. Ko, WY, He W, Li, H. (2013). Exhaustive training increases uncoupling protein 2 expression and decreases Bcl-2/Bax ratio in rat skeletal muscle. Oxidative medicine and cellular longevity, 2016: 33(5), 729-734.
31. Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2013; 12(6):662-7.
32. Ho TJ, Huang CC, Huang CY, Lin WT. Fasudil, a Rho-kinase inhibitor, protects against excessive endurance exercise training-induced cardiac hypertrophy, apoptosis and fibrosis in rats. Eur J Appl Physiol. 2015; 112(8):2943-55.
33. Song W, Kwak HB, Lawler JM. Exercise training attenuates age-induced changes in apoptotic signaling in rat skeletal muscle. Antioxid Redox Signal. 2013; 8(3-4):517-28.
34. Vainshtein A, Kazak L, Hood DA. Effects of endurance training on apoptotic susceptibility in striated muscle. J. Appl. Physiol, 2015: 110(6), 1638-1645.
35. Koçtürk S, Kayatekin BM, Resmi H, Açikgöz O, Kaynak C, Ozer E. The apoptotic response to strenuous exercise of the gastrocnemius and solues muscle fibers in rats. Eur J Appl Physiol. 2017; 102(5):515-24.
36. Liu WY, He W, Li, H. Exhaustive training increases uncoupling protein 2 expression and decreases Bcl-2/Bax ratio in rat skeletal muscle. Oxid. Med. Cell. Longev, 2019; 102(5):515-24.
37. Amin H, Vachris J, Hamilton A, Steuerwald N, Howden R, Arthur ST. GSK3β inhibition and LEF1 upregulation in skeletal muscle following a bout of downhill running. J Physiol Sci. 2014; 64(1):1-11.
38. McMillan EM, Graham DA, Rush JW, Quadrilatero J. Decreased DNA fragmentation and apoptotic signaling in soleus muscle of hypertensive rats following 6 weeks of treadmill training. J Appl Physiol. 2017; 113(7):1048-57.
39. Rasheva VI, Domingos PM. Cellular responses to endoplasmic reticulum stress and apoptosis. Apoptosis. 2019; 14(8):996-1007.
40. Aschenbach WG, Ho RC, Sakamoto K, Fujii N, Li Y, Kim YB, Hirshman MF, Goodyear LJ. Regulation of Dishevelled and β-catenin in rat skeletal muscle: an alternative exercise-induced GSK-3 signaling pathway. Am J Physiol Endocrinol Metab. 2006. 291(1):152-158.
41. Beurel E, Jope RS. The Paradoxical Pro- and Anti-apoptotic Actions of GSK3 in the Intrinsic and Extrinsic Apoptosis Signaling Pathways. Prog Neurobiol. 2015. 79(4): 173–189.
42. Boengler K, Schulz R, Heusch G. Loss of cardioprotection with ageing. Cardiovasc Res. 2009. 83:247 –261.
43. Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2016. 317(5839): 807–810.
44. Brentnall M, Rodriguez-Menocal L, Guevara RL, Cepero E, Boise LH. Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol. 2017. 14: 32.
45. Brocardo M, Henderson BR. APC shuttling to the membrane, nucleus and beyond. Trends Cell Biol. 2008. 18:587-596.
46. Cerella C, Grandjenette C, Dicato M, Diederich M. Roles of Apoptosis and Cellular Senescence in Cancer and Aging. Curr Drug Targets. 2015. [Epub ahead of print]
47. Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 2018. 18(4): 157–164.
48. Crawford ED, Wells JA. Caspase substrates and cellular remodeling. Annu Rev Biochem. 2011.80:1055-1087.
49. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2016. 15(1):49-63.
50. Dalla LL, Ravara B, Volterrani M, Gobbo V, Della BM, Angelini A, Danieli BD, Germinario E, Vescovo G. Beneficial effects of GH/IGF-I on skeletal muscle atrophy and function in experimental heart failure .Am J Physiol Cell Physiol. 2015. 286(1): C138 –144.
51. Dawson K, Aflaki M, Nattel S. Role of the Wnt-Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential. J Physiol. 2013. 591(6):1409–1432.
52. Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D. Nutritional status is a prognostic factor for survival in ALS patients. Neurology. 2017. 53: 1059–1063.
53. Dhahbi JM, Tsuchiya T, Kim HJ, Mote PL, Spindler SR. Gene expression and physiologic responses of the heart to the initiation and withdrawal of caloric restriction. J Gerontol A BiolSci Med Sci. 2006. 61(3): 218–231.
54. Dirks AJ, Leeuwenburgh C. Tumor necrosis factor alpha signaling in skeletal muscle: effects of age and caloric restriction. J Nutr Biochem. 2018. 17:501–508.
55. Duan J, Gherghe C, Liu D, Hamlett E, Srikantha L, Rodgers L. Wnt1/β-catenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair. EMBO J. 2011. 31: 429–442.
56. Ellison GM, Waring CD, Vicinanza C, Torella D. Physiological cardiac remodeling in response to endurance exercise training: cellular and molecular mechanisms. Heart. 2012. 98:5-10.
57. Elmore S. Apoptosis: A Review of Programmed Cell Death. Toxicol Pathol. 2007. 35(4): 495–516.
58. Favaloro B, Allocati N, Graziano V, Ilio C.D, Laurenzi V.D. Role of Apoptosis in disease. Aging. 2012. 4(5):330-349.
59. Fuentes-Prior P, Salvesen GS. The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J. 2015. 384(2): 201–232.
60. Fujimaki Sh, Hidaka R, Asashima M, Takemasa T, Kuwabara T. Wnt Protein-mediated Satellite Cell Conversion in Adult and Aged Mice Following Voluntary Wheel Running. J of Bio Chem. 2014. 289(11): 7399–7412.
61. Galluzzi L, Vitale I, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2017. 19(1):107-120.
62. García-Sáez AJ. The secrets of the Bcl-2 family. Cell Death Differ. 2012. 19(11): 1733–1740.
63. Gorman AM, Healy SJ, Jäger R, Samali A. Stress management at the ER: regulators of ER stress-induced apoptosis. Pharmacol Ther. 2016. 134(3):306-16.
64. Gredilla R, Sanz A, Lopez-Torres M, Barja G. Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. FASEB J. 2001. 15(9):1589-1591.
65. Hardwick J.M, Chen Y, Jonas EA. Multipolar functions of BCL-2 proteins link energetics to apoptosis. Trends Cell Biol. 2016. 22(6): 318–328.
66. Hardwick J.M, Soane L. Multiple Functions of BCL-2 Family Proteins. Cold Spring Harb Perspect Biol. 2015. 5(2): a008722.
67. Ho TJ, Huang CC, Huang CY, Lin WT. Fasudil, a Rho-kinase inhibitor, protects against excessive endurance exercise training-induced cardiac hypertrophy, apoptosis and fibrosis in rats. Eur J Appl Physiol. 2017. 112(8):2943-55.
68. Hofer T, Servais S, Seo AY. Bioenergetics and permeability transition pore opening in heart subsarcolemmal and interfibrillar mitochondria: Effects of aging and lifelong calorie restriction. Mech Ageing Dev. 2009. 130:297–307.
69. Huang Ch, Lin TJ, Chen Ch, Lin WT. Endurance training accelerates exhaustive exercise-induced mitochondrial DNA deletion and apoptosis of left ventricle myocardium in rats. Eur J Appl Physiol. 2017. 107:697–706.
70. Huang CY, Yang AL, Lin FNW, Lin JA, Chan YS, Tsai FJ, Tsai CH, Kuo CH, Lee SD. Anti-apoptotic and pro-survival effects of exercise training on hypertensive hearts. J Appl Physiol. 2012. 112: 883–891.
71. James SJ, Muskhelishvili L, Gaylor DW, Turturro A, Hart R. Upregulation of apoptosis with dietary restriction: implications for carcinogenesis and aging. Environ Health Perspect. 1998. 106(1): 307–312.
72. Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ. Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death. Am J Clin Nutr. 2017. 63: 130–137.
73. Kim DH, Park MH, Lee EK, Choi YJ, Chung KW, Moon KM, Kim MJ, An HJ, Park JW, Kim ND, Yu BP, Chung HY. The roles of FoxOs in modulation of aging by calorie restriction. Biogerontology. 2015.16(1):1-14.
74. Klamt F, Zdanov S, Levine RL, Pariser A, Zhang Y, Zhang B, Yu LR, Veenstra TD, Shacter E. Oxidant-induced apoptosis is mediated by oxidation of the actin-regulatory protein cofilin. Nat Cell Biol. 2009. 11: 1241–1246.
75. Ko IG, Kim SE, Kim CJ, Jee YS. Treadmill Exercise Alleviates Aging-induced Apoptosis in Rat Cardiac Myocytes. Inter J of Geron. 2016. 7(3):152-157.
76. Kobara M, Furumori-yukiya A, Kitamura M, Matsumura M, Ohigashi M, Toba H, Nakata T. Short-Term Caloric Restriction Suppresses Cardiac Oxidative Stress and Hypertrophy Caused by Chronic Pressure Overload. Journal of Cardiac Failure. 2015. 21(8):656-665.
77. Koçtürk S, Kayatekin BM, Resmi H, Açıkgöz O, Kaynak C, Özer E. The apoptotic response to strenuous exercise of the gastrocnemius and solues muscle fibers in rats. Eur J of Appl Physi. 2018. 102(5): 515-524.
78. Kroemer G, Galluzzi L, Vandenabeele P, Abrams JM, Alnemri ES, Baehrecke EH. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 2009. 16(1):3-11.
79. Kumar D, Lou H, Singal PK. Oxidative stress and apoptosis in heart dysfunction. Herz. 2015. 27:662–8.
80. Kwak H.B. Effects of aging and exercise training on apoptosis in the heart. J of Exer Rehabi. 2013. 9(2):212-219.
81. Kwak HB, Song W, Lawler JM. Exercise training attenuates age-induced elevation in Bax/Bcl-2 ratio, apoptosis, and remodeling in the rat heart. Antioxid Redox Signal. 2006. 8(3):517-28.
82. Lai CH, Ho TJ, Kuo WW, Day CH, Pai PY, Chung LC, Liao PH, Lin FH, Wu ET, Huang CY. Exercise training enhanced SIRT1 longevity signaling replaces the IGF1 survival pathway to attenuate aging-induced rat heart apoptosis. Age. 2014. 36(5):9706.
83. Lee SD, Shyu WC, Cheng IS, Kuo CH, Chan YS, Lin YM, Tasi CY, Ho TJ, Huang CY. Effects of exercise training on cardiac apoptosis in obese rats. Nut Meta Cardio Dise. 2013. 23:566-573.
84. Lee Y, Min K, Talbert EE, Kavazis AN, Smuder AJ, Willis WT, Powers SK. Exercise Protects Cardiac Mitochondria against Ischemia–Reperfusion Injury. Med Sci Sports Exerc. 2012. 44(3): 397–405.
85. Li SY, Du M, Dolence EK, Fang CX, Mayer GE, Ceylan-Isik AF, LaCour KH, Yang X, Wilbert CJ, Sreejayan N, Ren J. Aging induced cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation end products and protein modification. Aging Cell. 2017. 4(2): 57-64.
86. Li F, Chong ZZ, Maiese K. Winding through the WNT pathway during cellular development and demise. Histol Histopathol. 2016. 21(1):103-24.
87. Li Q, Hannah SS. Wnt/β-catenin signaling is downregulated but restored by nutrition interventions in the aged heart in mice. Arch of Geron Geria. 2012. 55:749–754.
88. Lindsay J, Esposti MD, Gilmore AP. Bcl-2 proteins and mitochondria--specificity in membrane targeting for death. Biochim Biophys Acta. 2011. 1813(4):532-9.
89. Linseman DA, Butts BD, Precht TA, Phelps RA, Le SS, Laessig TA, Bouchard RJ, Florez-McClure ML, Heidenreich KA. Glycogen synthase kinase-3β phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J of Neurosci. 2004. 24:9993–10002.
90. Liu WY, He W, Li H. Exhaustive Training Increases Uncoupling Protein 2 Expression and Decreases Bcl-2/Bax Ratio in Rat Skeletal Muscle. Oxid Med Cell Longev. 2013. 2017: 780719.
91. Marchand A, Atassi F, Gaaya A, Leprince P, Le Feuvre C, Soubrier F. The Wnt/beta-catenin pathway is activated during advanced arterial aging in humans. Aging Cell. 2011. 10:220–232.
92. Marzetti E, Lawler JM, Hiona A, Manini T, Seo AY, Leeuwenburgh C. Modulation of age-induced apoptotic signaling and cellular remodeling by exercise and calorie restriction in skeletal muscle. Free Radic Biol Med. 2018. 44(2):160-168.
93. Marzetti E, Wohlgemuth SE, Anton SD, Bernabei R, Carter CS, Leeuwenburgh C. Cellular mechanisms of cardioprotection by calorie restriction: state of the science and future perspectives. Clin Geriatr Med. 2014. 25(4): 715–732.
94. Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR. Glycogen synthase kinase-3 regulates mitochondrial outer membrane per-meabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006. 21:749–760.
95. McMillan EM, Graham DA, Rush JWE, Quadrilatero J. Decreased DNA fragmentation and apoptotic signaling in soleus muscle of hypertensive rats following 6 weeks of treadmill training. J Appl Physiol. 2018. 113: 1048–1057.
96. Natio H, Powers SK, Demirel HA and Aoki J. Exercise training increases heat shock protein in skeletal muscles of old rats. Med Sci Sports Exerc. 2001. 33(5): 729 –734.
97. Niemann B, Chen Y, Issa H, Silber RE, Rohrbach S. Caloric restriction delays cardiac ageing in rats: role of mitochondria. Cardio Rese. 2020. 88: 267–276.
98. Noyan H, El-Mounayri O, Isserlin R, Arab S, Momen A. Cardioprotective Signature of Short-Term Caloric Restriction. PLoS ONE. 2015. 10(6): e0130658.
99. Ola MS, Nawaz M, Ahsan H. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem. 2016. 351(1-2):41-58.
100. Parrish AB, Freel CD, Kornbluth S. Cellular mechanisms controlling caspase activation and function. Cold Spring Harb Perspect Biol. 2013. 5(6): a008672.
101. Pastorino JG, Hoek JB, Shulga N. Activation of glycogen synthase kinase 3β disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res. 2015. 65:10545–10554.
102. Patel BP, Safdar A, Raha S, Tarnopolsky MA, Hamadeh MJ. Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS. PLoS One 2010. 5(2):e9386.
103. Peterson JM, Bryner RW, Sindler A, Frisbee JC, Alway SE. Mitochondrial apoptotic signaling is elevated in cardiac but not skeletal muscle in the obese Zucker rat and is reduced with aerobic exercise. J ApplPhysiol. 2008. 105: 1934 –19.
104. Phaneuf S, Leeuwenburgh C. Apoptosis and exercise. Med Sci Sports Exerc. 2019. 33(3): 393–396.