Resistance training is associated with various adaptations in the organs of the body [1]. However, functional adaptation and morphology can be reduced after a short period of detraining [2]. Detraining can be considered a partial or complete interruption of an exercise program or a partial or complete loss of exercise benefits in response to an inadequate exercise stimulus [3]. Some studies have shown that metabolic and functional adaptation of exercise programs can be reduced even after short periods of inactivity due to illness and vacations [4]. Detraining causes loss of various adaptations, including cardiovascular [3].
Potassium channels and mitochondrial biogenesis are among the cardiovascular adaptations affected by exercise [5, 6]. ATP-sensitive potassium (KATP) channels are expressed in various tissues such as the heart [7]. In the cardiovascular system, these channels play a protective role in metabolic stresses such as hypoxia and ischemia (In these conditions, the intracellular ATP concentrations decrease). In the heart, potassium channels reduce the duration of action potential and intracellular potassium loss [8].
Suppression of potassium channels inhibits the growth and development of pathological hypertrophy in the heart. The activation of KATP channels by reducing cell death and tissue damage protects the heart [9]. Cardiac myocytes have two different types of ATP-sensitive potassium channels. There is a classic type in sarcoma (sarcK ATP) and another type in the mitochondrial inner membrane (mitoK ATP) [10]. It seems that exercise can positively affect these channels. Molecular studies have determined that ATP-sensitive potassium channels of the membrane surface are composed of octameric complexes consisting of four pore subunits (KIR6.2) and four regulatory Sulfonylurea Receptor (SUR) subunits. Two isoforms of inward-rectifier potassium channels (KIR) (KIR6.1 and KIR6.2) and three isoforms of SUR (SUR1, SUR2A, and SUR2B) have been identified [10]. Some research has shown that aerobic exercise affects SUR and KIR content [11, 12]. 
In the study of Wang et al., who examined the effect of 8 weeks of aerobic exercise in male and female mice, it was found that exercise increased SUR and KIR6.2 [11]. Brown   et al. also reported an increase in potassium channels after 12 weeks of regular aerobic exercise [12]. The other effects of exercises are not well understood. For example, there are no clear results for resistance training. Also, the effect of detraining after exercise on potassium channels is unknown. However, some studies have shown that the effect of exercise-induced bradycardia (which can be due to the function of these channels) is reduced by detraining [13, 14]. Junior et al. found that eight weeks of exercise improved markers associated with hypertension and cardiac hypertrophy, including skeletal α-actin and α/β-MHC ratio, but four weeks of detraining caused the loss of these adaptations [14]. 
Another important adaptation resulting from exercise is an increase in mitochondrial size and density. Peroxisome Poliferator-activated receptor Gamma Coactivator 1-alpha (PGC1α) plays an essential role in this regard [15]. PGC1α is expressed in the heart and skeletal muscles to provide energy in response to exercise [16] and plays an essential role in regulating mitochondrial biogenesis [17]. Increased PGC1α stimulates transcription of the nuclear respiratory factor and leads to increased expression of mitochondrial transcription factor A (TFAM) and other mitochondrial subunits of the electron transport chain. TFAM is the target gene for Nuclear Respiratory Factor 1 (NRF1), which plays a vital role in coordinating interactions between mitochondria and the nucleus [17]. This gene is a mitochondrial transcription factor that is a key activator in transcription [17]. Limited studies have shown that aerobic and resistance exercise increases PGC1α in skeletal muscle and heart muscles [18, 19]. 
Increased TFAM in skeletal muscle due to aerobic exercise has also been reported [20]. The available findings show that mitochondrial adaptations in skeletal muscle decrease by detraining after aerobic training and resistance training [21, 22]. However, no specific results have been reported on the effects of detraining on mitochondrial biogenesis factors (PGC1α and TFAM) in cardiac cells.
Cardiovascular adaptation seems to be proportionate with exercise characteristics such as intensity and duration of exercise, so inactivity and detraining may weaken the heart and cardiovascular system. This problem becomes more apparent in more prepared people. Therefore, considering the importance of potassium channels and mitochondrial biogenesis factors during training and detraining, as well as research limitations in this field, this study aimed to investigate the effect of a detraining period after resistance training on immunohistochemical expression of ATP-sensitive potassium channels and mitochondrial biogenesis of heart tissue in male rats.

This study was experimental with a control group. Thirty male Wistar rats (according to previous sources) [12, 18] were purchased at the age of five weeks and transferred to the place of keeping laboratory animals at the Department of Sports Physiology, Mazandaran University, Mazandaran Province, Iran. Then, they were randomly divided into four groups (control group, control-detraining group, the resistance-training group and, the resistance training-detraining group).
The control group at the beginning of the investigation was killed, and the control-detraining group was placed in cages with free access to water and food and did not engage in exercise. The duration of the inactivity in the control-detraining group lasted three weeks longer than the control group. The resistance-training group and the resistance training-detraining group performed the resistance training protocol according to Table 1 during the research. The resistance-detraining group lacked any training for three weeks after completing the training period. At the end of the study, the rats were first anesthetized and, then, using surgical instruments, their heart tissue was extracted and immediately placed in formalin fluid. 



The groups were briefly treated as follows:
- Control group: They were killed at the beginning of the investigation.
 - Resistance-training group: They were performed eight weeks of resistance training and killed after eight weeks.
- Resistance training-detraining group: They were performed eight weeks of resistance training and then detrained for three weeks and then were killed.
- Control -detraining group: They did not do any activities during the research (11 weeks) and were killed after that.
Strength training program
In the Scott strength training, to condition the rats, they wore the vest for 20 minutes every day with the help of the researcher. Also, in the first week, they were stood on both feet three sets of 10 in the Scott position with the help of the researcher. In the second week, to familiarize the subjects, they were placed on a squat machine made by Mirdar and Sadoughi (2018) and performed three sets of 10 squats every day without weights. To stimulate the movement, a gentle electric shock was induced on the bottom of the device and the sole of the subject’s foot.
The training period of rats was eight weeks, which was performed in sets of 10. The intensity of training in the first three weeks, the end of the fourth week, and the end of the eighth week of the training protocol was at most one maximum repetition (1RM) of the subjects. Then, according to Table 1, the protocol was implemented in two 4-week periods. The weight moved by the subjects was determined by taking into account the weight of the vest, the lever of the measuring device, and the strength and intensity of the exercise. Apart from the main activity time, 5 minutes were provided for a warm-up and 5 minutes for cooling down. The Scott movement was started after wearing the vest with the researcher’s help.
Handgrip strength training was performed similar to the Scott training and with the handgrip machine. However, in the handgrip training, the subjects weightlessly hung from the machine in 3 sets of 10 in the first two weeks of acquaintance. The handgrip exercise was performed by pull up using weights attached to the subjects’ tails with the researcher’s support from the end of the tail without any help or force from the researcher. The subjects were separated from the machine and had an active rest between training sets. Apart from the main activity time, the subjects had 5 minutes to warm up and 5 minutes to cool down on the device with the researcher’s help [23].
Also, 1RM was calculated according to the displaced weight and the number of repetitions according to the Formula 1.
Formula (1):
A= (number of repetitions × 2) - 100
as a result:
1RM= A / 100 × displaced weight
Histopathology
After removing the desired tissue, it was fixed with 10% formalin Bowen solution. The use of this fixative during the tissue preparation process leads to better staining results. Then, to dehydrate the tissue, the sample was placed in 70%, 80%, and 90% and then absolute alcohol. In the molding stage, the paraffin-impregnated sample was placed in a mold filled with molten paraffin. While freezing the paraffin, the left sample inside was ready for cross-section. The sample was cut with a thickness of 5 to 10 µ by microtome.
Immunohistochemistry (IHC) method
The sample was washed with PBS in 3 steps and incubated in citrate buffer (pH: 9.1) for 20 minutes at 70°C. To recover the antigen, 2 N hydrochloric acid was poured on the samples for 30 minutes. The cells were then washed with PBS. Also, 0.3% Triton was used for 30 minutes to permeate the cell membranes and then washed with Phosphate-Buffered Saline (PBS). Then, 10% goat serum was added as additional background dye for 30 minutes to block the secondary antibody reaction. The samples were then transferred from the incubator to a dark room, and after four washes, DAPI was added to them. They were immediately removed, and PBS was poured on the samples. In the last step, the sample was observed by Labomed TCM400 fluorescent microscope.
Also, we used Kir6.2: Sc-390104 laboratory kit (Santa Cruz Biotechnology, Inc., USA), SUR2: MBS8242984 (MyBioSource, USA), PGC1: ab54481 (Abcam, UK), and TFAM: LS-B9989 (LifeSpan, BioSciences, USA) .

Statistical method
In the present study, the Shapiro-Wilk test was used to investigate the normality of data distribution. One-way analysis of variance and Tukey’s post hoc test were also used to examine the research variables. All investigations were performed at the significance level of α ≥0.05 using Prism 5.0.

The analysis of variance showed significant differences between the groups in terms of expression of KIR6.2, SUR2a, PGC1α, and TFAM in the heart tissue of male rats (P=0.001). Tukey post hoc test also showed the expression of KIR6.2, SUR2a, PGC1α, and TFAM was significantly increased in control-detraining (P=0.001), resistance training (P=0.001), and resistance-detraining (P=0.001) groups compared to the control group.
Also, in the resistance training group compared to the control-detraining group, the increased expression of KIR6.2, SUR2a, PGC1α, and TFAM (P=0.001), and in the resistance-detraining group compared to the resistance training group (P=0.001), the decreased expression was reported. Regarding the expression of KIR6.2, SUR2a, and TFAM, no significant difference was observed between the control-detraining group and the resistance-detraining group (P≥0.05) (Figure 1, 2, 3 & 4). However, PGC1α expression was higher in the resistance-detraining group compared to the control-detraining group (P=0.001). 

This study aimed to evaluate the effect of a detraining period after resistance training on the expression of KIR6.2, SUR2a, TFAM, and PGC1α in the heart tissue of young male rats. The results showed that resistance training had a significant effect on potassium channels. Accordingly, the resistance training group had high levels of KIR6.2 and SUR2a. And the resistance-detraining group, control-detraining group, and control group were in the next ranks in terms of KIR6.2 and SUR2a expression.
No clear results were found on the effect of resistance training on these proteins. But research by Wang et al. showed that regular endurance training significantly increases SUR myocytes and KIR content [11]. Brown  et al. reported that KIR protein increased by 58% and SUR by 75% in the exercise group [12]. Research by Kralovich et al. also showed that intermittent exercise increases SUR2a in the heart tissue of mice with heart failure [24].
There were no clear results on detraining effects after an exercise on potassium channels, but some studies had shown that the effect of chronic exercise bradycardia was reversed when rats were detrained for two weeks [13]. Consistent regulation of ATP-sensitive potassium channel expression in response to exercise can be an essential adaptation element [25]. In this regard, Kane et al. reported that the elimination of ATP-sensitive channels during exercise leads to heart failure [26]. Zingman et al. reported that an exercise-induced increase in ATP channel expression increases the action’s speed and magnitude and shortens the action potential in response to heart rate acceleration [25]. Recent studies using Kir6.2-deficient mice have shown that disruption of KATP channel activity leads to activation of calcineurin-dependent pathways, which in turn increases the nuclear accumulation of hypertrophic transcription factors MEF2 and NF-AT [27, 28].
Exercise activates SUR2a gene transcription through the c-Jun / NH2 kinase terminal signal cascade pathway [25]. Although the precise definition of the mechanism underlying KATP channel re-regulation by exercise requires further study, some studies have shown that increased ABCC9 transcription increases SUR2A production and increases the expression of KATP functional channels in response to short-term exposure to exercise [25]. In the case of KIR6.2, its activity in Vascular Smooth Muscle (VSM) can be modulated by PKC (inhibition) and PKA (activation) signaling pathways and metabolic stress such as hypoxia and ischemia [29].
The significant point is the declining trend in potassium channel expression after detraining. In this study, there was no significant difference between the control-detraining group and the resistance-detraining group in terms of KIR6.2 and SUR2a expression. In other words, trained rats can lose cardiac KIR6.2 and SUR2a levels in the short term if left detrained and approach control-detraining conditions. Considering that shear stress is one of the factors that increase the expression of potassium channels [30] and is affected by exercise and detraining [31], one reason for the decrease in the expression of these channels can be attributed to the reduction of shear stress. On the other hand, increasing or decreasing potassium channels also affect mitochondrial biogenesis factors such as PGC1α [32].
Our results showed that resistance training increases the expression of PGC1α. However, detraining after resistance training reduces it. Baghadam et al., in the study of the effect of resistance training on irisin and expression of PGC1α PGC1α gene in the heart muscle of diabetic rats, showed that resistance training causes a significant increase in PGC1α [19]. Shabani et al. investigated the effect of eight weeks of aerobic exercise on the expression of PGC1α and VEGF in the heart muscle of healthy male mice and did not report a significant change in PGC1α [18]. PGC1α has two isoforms, alpha and beta, and by activating a group of transport agents, it increases mitochondrial biogenesis and is activated by activating factors [19]. Kang et al. reported that PGC1α expression plays an essential role in preventing skeletal muscle atrophy and indicates an increase in mitochondrial biogenesis and a decrease in oxidative damage [33].
Studies have shown that physical activity increases PGC1α expression via the beta-adrenergic receptor / cAMP pathway [34]. Exercise and increased energy demand lead to increased AMP, calcium concentration of free phosphate groups, and intracellular reactive oxygen species. This substrate activates some intracellular signals, including the calcium-dependent protein calmodulin, AMP-activated protein kinase (AMPK), and mitogen-activated kinase P38, which plays an essential role in the upregulation of PGC1α activity, followed by mitochondrial biogenesis [33].
Potassium channel activity is also required to maintain PGC-1α expression under stress. Suppression of KATP channel activity disrupts PGC1α expression through the FOXO1 signaling pathway [32]. Akt may regulate PGC1α gene expression through phosphorylation and phos-FOXO1 nuclear release. Previous studies have shown that disruption of KATP channel activity in neonatal myocytes increases Akt phosphorylation [32]. Also, our results showed that following the increase in KIR6.2 and SUR2a after resistance training, the expression of PGC-1α increases. The PGC-1α expression also decreases following detraining and decreased potassium channel expression.
PGC-1α modulates mitochondrial biogenesis by direct correlation of transcription factors such as Nuclear Respiratory Factor (NRF) and Estrogen Receptor (ERR) [35]. The binding sites for the NRF-1 monomer and the NRF-2 heterotrimer (also known as GABP) are found in the promoters of most respiratory chain genes. The effect of overexpression of NRF-1 or NRF-2 in cardiac tissue has not been evaluated so far. However, overexpression of NRF-1 in skeletal muscle increased oxidative phosphorylation (OXPHOS) genes. PGC-1α physically interacts with both NRF-1 and -2 and stimulates their activity on mitochondrial genes [36, 37]. Increased PGC1α also stimulates nuclear respiration factor transcription and leads to increased expression of mitochondrial transcription factor (TFAM) and other mitochondrial subunits of the electron transport chain [17].
 The present study showed that resistance training increases TFAM in heart cells of healthy rats. But detraining significantly reduced it. Popov et al. investigated the effect of two months of aerobic exercise on skeletal muscle TFAM in human samples and reported its significant increase [20]. Islam et al. reported similar results [38].
 Interactions between the nuclear genome and mitochondria are mediated in part by encoded nuclear proteins such as TFAM, TFB1, and TFB2. PGC-1α induces the genes of these three proteins through the induction and activation of NRF-1 and NRF-2. TFAM is a high-active transcription factor group responsible for the replication and transcription of mitochondrial DNA. Impairment of TFAM target specifically in cardiac tissue leads to a significant reduction in electron transport capacity, spontaneous cardiomyopathy, and heart failure. In contrast, increased TFAM expression in cardiac tissue protects against heart failure due to myocardial infarction [39].
Studies have shown that ROS, through binding to mtDNA, leads to degradation and reduces its function. Mitochondrial transcription factor (TFAM) binds to and covers the mtDNA and protects against ROS and its degradation while increasing mitochondrial function [40]. Exercise increases TFAM and increases mitochondrial biogenesis by increasing PGC1α. However, detraining can reverse this trend [40]. The present study results also showed that detraining reduced PGC1α and TFAM in the heart cells of healthy rats. It is possible that detraining reduces mitochondrial biogenesis by increasing factors such as ROS and decreasing PGC1α and TFAM.

Finally, the results of this study show that resistance training increases the potassium channels of KIR6.2 and SUR2a and increases the mitochondrial biogenesis of PGC1α and TFAM of heart cells. Resistance training is effective in increasing mitochondrial biogenesis through PGC1α and TFAM by increasing KIR6.2 and SUR2a. However, cardiac adaptations resulting from resistance training can be returned to baseline due to detraining, which reduces the expression of potassium channels and factors that increase mitochondrial biogenesis.

This study was approved by the Ethics Committee of the Ardabil University of Medical Sciences (Code: IR.ARUMS.REC.1398.555).

This article is an extracted from the PhD. dissertation of the first author at the Department of Exercise Physiology, Faculty of Educational Sciences and Psychology, University of Mohaghegh Ardabili, Ardabil. 

All authors equally contributed to preparing this article.

The authors declared no conflict of interest.
 

References

1. Melo S, da Silva Júnior N, Barauna V, Oliveira E. Cardiovascular adaptations induced by resistance training in animal models. International journal of Medical Sciences. 2018; 15(4):403-10. [DOI:10.7150/ijms.23150] [PMID] [PMCID]

2. Toraman NFو Ayceman N. Effects of six weeks of detraining on retention of functional fitness of old people after nine weeks of multicomponent training. British Journal of Sports Medicine. 2005; 39(8):565-8. [DOI:10.1136/bjsm.2004.015586] [PMID] [PMCID]

3. Leitão L, Pereira A, Mazini M, Venturini G, Campos Y, Vieira J, et al. Effects of three months of detraining on the health profile of older women after a multicomponent exercise program. International Journal of Environmental Research and Public Health. 2019; 16(20):3881. [DOI:10.3390/ijerph16203881] [PMID] [PMCID]

4. Fragala MS, Cadore EL, Dorgo S, Izquierdo M, Kraemer WJ, Peterson MD, et al. Resistance training for older adults: Position statement from the national strength and conditioning association. The Journal of Strength & Conditioning Research. 2019; 33(8):2019-52. [DOI:10.1519/JSC.0000000000003230] [PMID]

5. Calderón Montero F, Benito Peinado P, Di Salvo V, Pigozzi F, Maffulli N. Cardiac adaptation to training and decreased training loads in endurance athletes: A systematic review. British Medical Bulletin. 2007; 84(1):25-35. [DOI:10.1093/bmb/ldm027] [PMID]

6. Wang H, Bei Y, Lu Y, Sun W, Liu Q, Wang Y, et al. Exercise prevents cardiac injury and improves mitochondrial biogenesis in advanced diabetic cardiomyopathy with PGC-1α and Akt activation. Cellular Physiology and Biochemistry. 2015; 35(6):2159-68. [DOI:10.1159/000374021] [PMID]

7. Inagaki N, Gonoi T, Clement JP, Namba N, Inazawa J, Gonzalez G, et al. Reconstitution of IKATP: An inward rectifier subunit plus the sulfonylurea receptor. Science. 1995; 270(5239):1166-70. [DOI:10.1126/science.270.5239.1166] [PMID]

8. Minami K, Miki T, Kadowaki T, Seino S. Roles of ATP-sensitive K+ channels as metabolic sensors: Studies of Kir6. x null mice. Diabetes. 2004; 53(suppl 3):S176-80. [DOI:10.2337/diabetes.53.suppl_3.s176] [PMID]

9. Muntean DM, Kiss L, Jost N, Baczkó I. ATP-sensitive potassium channel modulators and cardiac arrhythmias: An update. Current Pharmaceutical Design. 2015; 21(8):1091-102. [DOI:10.2174/1381612820666141029102800] [PMID]

10. Rubaiy HN. The therapeutic agents that target ATP-sensitive potassium channels. Acta Pharmaceutica. 2016; 66(1):23-34. [DOI:10.1515/acph-2016-0006] [PMID]

11. Wang X, Fitts RH. Effects of regular exercise on ventricular myocyte biomechanics and KATP channel function. American Journal of Physiology-Heart and Circulatory Physiology. 2018; 315(4):H885-96. [DOI:10.1152/ajpheart.00130.2018] [PMID]

12. Brown DA, Chicco AJ, Jew KN, Johnson MS, Lynch JM, Watson PA, et al. Cardioprotection afforded by chronic exercise is mediated by the sarcolemmal, and not the mitochondrial, isoform of the KATP channel in the rat. The Journal of Physiology. 2005; 569(3):913-24. [DOI:10.1113/jphysiol.2005.095729] [PMID] [PMCID]

13. Bois P, Bescond J, Renaudon B, Lenfant J. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. British Journal of Pharmacology. 1996; 118(4):1051-7. [DOI:10.1111/j.1476-5381.1996.tb15505.x] [PMID] [PMCID]

14. Carneiro-Júnior MA, Quintão-Júnior JF, Drummond LR, Lavorato VN, Drummond FR, da Cunha DNQ, et al. The benefits of endurance training in cardiomyocyte function in hypertensive rats are reversed within four weeks of detraining. Journal of Molecular and Cellular Cardiology. 2013; 57:119-28. [DOI:10.1016/j.yjmcc.2013.01.013] [PMID]

15. Holloszy JO. Biochemical adaptations in muscle effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. Journal of Biological Chemistry. 1967; 242(9):2278-82. [DOI:10.1016/S0021-9258(18)96046-1]

16. Tadaishi M, Miura S, Kai Y, Kawasaki E, Koshinaka K, Kawanaka K, et al. Effect of exercise intensity and AICAR on isoform-specific expressions of murine skeletal muscle PGC-1α mRNA: A role of β2-adrenergic receptor activation. American Journal of Physiology-Endocrinology and Metabolism. 2010; 300(2):E341-9. [DOI:10.1152/ajpendo.00400.2010] [PMID]

17. Wang C, Li Z, Lu Y, Du R, Katiyar S, Yang J, Fu M, Leader JE, Quong A, Novikoff PM. Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function. Proceedings of the National Academy of Sciences. 2006; 103(31):11567-72. [DOI:10.1073/pnas.0603363103] [PMID] [PMCID]

18. Shabani M, Choobineh S, Kordi MR, Afghan M. [The effect of 8 weeks of high intensity interval training on the expression of PGC-1α and VEGF genes in myocardial muscle of male healthy rats (Persian)]. Journal of Sport Biological Sciences. 2016; 8(2):169-76. [doi:10.22059/JSB.2016.59092]

19. Baghadam M, Mohammadzadeh سalamat Kh, Azizbeigi K, Baesi K. [The effect of resistance training on IRISIN and gene expression of PGC1α in the cardiac muscle in STZ-Induced diabetic rats (Persian)]. Community Health Journal. 2018; 12(3):58-64. http://chj.rums.ac.ir/article_85033.html

20. Popov DV, Lysenko EA, Bokov RO, Volodina MA, Kurochkina NS, Makhnovskii PA, et al. Effect of aerobic training on baseline expression of signaling and respiratory proteins in human skeletal muscle. Physiological reports. 2018; 6(17):e13868. [DOI:10.14814/phy2.13868] [PMID] [PMCID]

21. Wibom R, Hultman E, Johansson M, Matherei K, Constantin-Teodosiu D, Schantz P. Adaptation of mitochondrial ATP production in human skeletal muscle to endurance training and detraining. Journal of Applied Physiology. 1992; 73(5):2004-10. [DOI:10.1152/jappl.1992.73.5.2004] [PMID]

22. Lee H, Kim K, Kim B, Shin J, Rajan S, Wu J, et al. A cellular mechanism of muscle memory facilitates mitochondrial remodelling following resistance training. The Journal of Physiology. 2018; 596(18):4413-26. [DOI:10.1113/JP275308] [PMID] [PMCID]

23. Kodesh E, Zaldivar F, Schwindt C, Tran P, Yu A, Camilon M, et al. A rat model of exercise-induced asthma: a nonspecific response to a specific immunogen. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2011; 300(4):R917-24. [DOI:10.1152/ajpregu.00270.2010] [PMID] [PMCID]

24. Kraljevic J, Høydal MA, Ljubkovic M, Moreira JB, Jørgensen K, Ness HO, et al. Role of KATP channels in beneficial effects of exercise in ischemic heart failure. Medicine and Science in Sports and Exercise. 2015; 47(12):2504-12. [DOI:10.1249/MSS.0000000000000714] [PMID]

25. Zingman LV, Zhu Z, Sierra A, Stepniak E, Burnett CM-L, Maksymov G, et al. Exercise-induced expression of cardiac ATP-sensitive potassium channels promotes action potential shortening and energy conservation. Journal of Molecular and Cellular Cardiology. 2011; 51(1):72-81. [DOI:10.1016/j.yjmcc.2011.03.010] [PMID] [PMCID]

26. Kane GC, Behfar A, Yamada S, Perez-Terzic C, O’Cochlain F, Reyes S, et al. ATP-sensitive K+ channel knockout compromises the metabolic benefit of exercise training, resulting in cardiac deficits. Diabetes. 2004, 53(suppl 3):S169-75. [DOI:10.2337/diabetes.53.suppl_3.S169] [PMID]

27. Kane GC, Behfar A, Dyer RB, O’Cochlain DF, Liu X-K, Hodgson DM, et al. KCNJ11 gene knockout of the Kir6. 2 K ATP channel causes maladaptive remodeling and heart failure in hypertension. Human Molecular Genetics. 2006; 15(15):2285-97. [DOI:10.1093/hmg/ddl154] [PMID]

28. Yamada S, Kane GC, Behfar A, Liu XK, Dyer RB, Faustino RS, et al. Protection conferred by myocardial ATP-sensitive K+ channels in pressure overload-induced congestive heart failure revealed in KCNJ11 Kir6. 2-null mutant. The Journal of Physiology. 2006; 577(3):1053-65. [DOI:10.1113/jphysiol.2006.119511] [PMID] [PMCID]

29. Cui Y, Tinker A, Clapp LH. Different molecular sites of action for the KATP channel inhibitors, PNU-99963 and PNU-37883A. British Journal of Pharmacology. 2003; 139(1):122-8. [DOI:10.1038/sj.bjp.0705228] [PMID] [PMCID]

30. Chatterjee S, Al-Mehdi A-B, Levitan I, Stevens T, Fisher AB. Shear stress increases expression of a KATP channel in rat and bovine pulmonary vascular endothelial cells. American Journal of Physiology-Cell Physiology. 2003; 285(4):C959-67. [DOI:10.1152/ajpcell.00511.2002] [PMID]

31. Wang JS, Li YS, Chen JC, Chen YW. Effects of exercise training and deconditioning on platelet aggregation induced by alternating shear stress in men. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005; 25(2):454-60. [DOI:10.1161/01.ATV.0000151987.04607.24] [PMID]

32. Hu X, Xu X, Huang Y, Fassett J, Flagg TP, Zhang Y, et al. Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload. Circulation Research. 2008; 103(9):1009-17. [DOI:10.1161/CIRCRESAHA.107.170795] [PMID] [PMCID]

33. Kang C, Ji LL. Role of PGC-1α signaling in skeletal muscle health and disease. Annals of the New York Academy of Sciences. 2012; 1271(1):110-7. [DOI:10.1111/j.1749-6632.2012.06738.x] [PMID] [PMCID]

34. Hamidie RDR, Yamada T, Ishizawa R, Saito Y, Masuda K. Curcumin treatment enhances the effect of exercise on mitochondrial biogenesis in skeletal muscle by increasing cAMP levels. Metabolism. 2015; 64(10):1334-47. [DOI:10.1016/j.metabol.2015.07.010] [PMID]

35. Huss JM, Torra IP, Staels B, Giguere V, Kelly DP. Estrogen-related receptor α directs peroxisome proliferator-activated receptor α signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Molecular and Cellular Biology. 2004; 24(20):9079-91. [DOI:10.1128/MCB.24.20.9079-9091.2004] [PMID] [PMCID]

36. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999; 98(1):115-24. [DOI:10.1016/S0092-8674(00)80611-X]

37. Baar K, Song Z, Semenkovich CF, Jones TE, Han D-H, Nolte LA, et al. Skeletal muscle overexpression of nuclear respiratory factor 1 increases glucose transport capacity. The FASEB Journal. 2003; 17(12):1666-73. [DOI:10.1096/fj.03-0049com] [PMID]

38. Islam H, Edgett BA, Gurd BJ. Coordination of mitochondrial biogenesis by PGC-1α in human skeletal muscle: A re-evaluation. Metabolism. 2018; 79:42-51. [DOI:10.1016/j.metabol.2017.11.001] [PMID]

39. Ikeuchi M, Matsusaka H, Kang D, Matsushima S, Ide T, Kubota T, et al. Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction. Circulation. 2005; 112(5):683-90. [DOI:10.1161/CIRCULATIONAHA.104.524835] [PMID]

40. Theilen NT, Kunkel GH, Tyagi SC. The role of exercise and TFAM in preventing skeletal muscle atrophy. Journal of Cellular Physiology. 2017; 232(9):2348-58. [DOI:10.1002/jcp.25737] [PMID] [PMCID]