Medical Hypotheses 82 (2014) 748–753

Contents lists available at ScienceDirect

Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy

The effect of exercise on epigenetic modifications of PGC1: The impact on type 2 diabetes Júlia M. Santos a,b,⇑, Shikha Tewari c, Sandra A. Benite-Ribeiro b a

Wayne State University, Detroit R&D, Detroit, MI, USA Federal University of Goiás, CAJ, Jataí, Brazil c Ram Manohar Lohia, Institute of Medical Science, Lucknow, India b

a r t i c l e

i n f o

Article history: Received 4 December 2013 Accepted 10 March 2014

a b s t r a c t The worldwide prevalence of diabetes type 2 is increasing and intramuscular accumulation of fatty acid metabolites is gradually becoming recognized as core features of this condition as lipotoxicity induces insulin resistance. Emerging evidences suggest that defects in mitochondria, key organelle in lipid metabolism, play a central role on insulin resistance. Mitochondria homeostasis is tightly regulated by a nucleus-mitochondria signaling pathway and peroxisome proliferator-activated receptor c coactivator1a (PGC1) is the master regulator of important mitochondria process. PGC1 is down regulated in insulin resistant skeletal muscle and abnormal posttranslational modification at histone, epigenetic modifications, is an important factor. Studies have demonstrated the benefits of regular exercise on improving insulin sensitivity however the mechanism for this outcome is not entirely identified. Moreover evidences point out the increase in PGC1 expression induced by exercise as an important element for the improvement of insulin sensitivity in skeletal muscle via increase in mitochondria density and glucose transporter expression (GLUT4). Therefore, we here proposed that aerobic exercise attenuates epigenetic modifications at PGC1 induced by high-energy diets and reduced physical activity, and that leads to inhibition/delay of type 2 diabetic onset. Ó 2014 Elsevier Ltd. All rights reserved.

Introduction Diabetes is complex disorder that constitutes a major problem of public health. Epidemiological data demonstrate that the prevalence of diabetes among adults was 285 million in 2010, and this value is predicted to reach 439 million by 2030 [1,2]. The incidence of global mortality attributed to diabetes in 2000 was 2.9 million of deaths, and in a country in development as Brazil diabetes is the fifth underlying cause of death affecting 2.5% of the population [3,4]. Furthermore, diabetic retinopathy is the leading cause of blindness in the working age, and is also responsible to 44% of end-stage renal failure and 60% of non-traumatic lower-limb amputations [5–7]. Type 2 diabetes, the predominant form that accounts for at least 90–95% of cases, is linked to changes in lifestyle (high-energy diets with reduced physical activity) and to the rise in overweight and obesity [3,6]. Type 2 diabetes is characterized by hyperglycaemia and altered lipid metabolism resultant by the incapability of pancreatic b cells ⇑ Corresponding author at: Wayne State University, 2727 Second Ave, Suite 4113 Detroit R&D, Detroit, MI 48201, USA. Tel.: +1 313 9800160. E-mail addresses: [email protected], juliamatzenbachersanto@hotmail. com (J.M. Santos). http://dx.doi.org/10.1016/j.mehy.2014.03.018 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.

to secrete adequate insulin and/or defect of insulin action due mainly by overweight, inactivity, age and genetic factors [3,8]. In myocytes and adiposites insulin acts as a trigger to induce glucose uptake by activating the translocation of glucose transporter 4 (GLUT4) to the cell membrane. GLUT4 in its quiescent condition is located in intracellular vesicles at the cytosol and a complex pathway is required to move to its target, the cell membrane [6,9]. Any disruption in this pathway affects glucose transport to the cytosol [10]. Nevertheless, apart from insulin other factors like muscle contraction and pharmacological agents also increase the amount of surface GLUT4 in skeletal muscle [6,11–13]. Moreover, a considerable amount of research has revealed that an acute bout of physical exercise enhances skeletal muscle glucose uptake and regular physical activity improves the ability of insulin to stimulate the glucose transporters at rest [6,8,11,14,15]. Despite of the cutting edge research on the field, the exact mechanism responsible for insulin resistance and the improvement of insulin response induced by exercise still not entirely identified. Insulin resistance Insulin induce glucose uptake by a complex pathway initiated by its binding with insulin receptor (IR). Insulin-IR binding

J.M. Santos et al. / Medical Hypotheses 82 (2014) 748–753

promotes the IR autophosphorylation that turns activate the insulin substrate receptor (IRS). Upon phosphorylation, IRS proteins interact with the regulatory subunit of phosphatidylinositol (PI)-3-kinase (PI3K), which catalyses the formation of the lipid product phosphatidylinositol 3,4,5-trisphosphate (PIP3), which regulates the activity of downstream proteins such as protein kinase B (PKB or AKT) and atypical protein kinase C (aPKC) [16,17]. AKT is a signaling protein for several insulin actions, including glycogen synthesis and GLUT4 translocation. The AKT substrate of 160KD (AS160), links the GLUT4 vesicle into the cytosol and when phosphorylated allows GLUT4 vesicle to move towards the membrane. The aPKC acts in parallel with AS160 and appears to activate motor proteins, such as kinesins, which contribute to vesicle migration to the cell membrane [6,18]. Until now a number of defects within the insulin cascade are associated with insulin resistance; however, reduced IRS-phosphorylation in response to insulin seems to be the most prominent defect in the cascade [10,19,20]. A common characteristic in the skeletal muscle that experiences insulin resistant is the increased accumulation of intramuscular lipid, and that raises the possibility that alterations in lipid metabolism influence insulin signaling. Studies in humans and rodents have demonstrated a strong relationship between increased intramuscular triacylglycerol (TAG) content and insulin resistance [21–23]. Moreover, reduction in insulin-mediated glucose uptake has been observed after acute elevations in plasma free fatty acid levels by lipid infusion in humans and rodents [24–26]. On the other hand, studies suggest that TAG may not be the single problem to impair in insulin action, but instead insulin resistance is caused by the accumulation of lipid intermediates such as long-chain acyl CoA (LCACoA), diacylglycerol (DAG) and ceramide [27]. The accumulation of these fatty acid metabolites within skeletal muscle activates a serine/threonine kinase cascade involving the novel protein kinase C (nPKC) isoforms, IkappaB kinase-b (IKK-b) and c-jun terminal amino kinase (JNK), which inhibit IRS signalling and Akt phosphorylation [28–30]. Altogether, these data indicate that strategies that limit the accumulation of fatty acid metabolites may prevent insulin resistance and the further development of diabetes type 2.

Mitochondria and insulin resistance – the role of PGC1 There may be multiple metabolic causes for increased sarcoplasm lipid accumulation in insulin-resistant state. Mitochondria are the main organelle responsible for lipid peroxidation therefore, its function seem critical in the fatty acid metabolites accumulation in the sarcoplasm [31,32]. Indeed the role of mitochondria dysfunction in insulin resistance has been well demonstrated in laboratory animal as well as in humans [32,33]. In addition, insulin-resistant individuals seem to contain approximately 30% fewer mitochondria in their skeletal muscle than age-matched healthy controls [34]. Mitochondria DNA (mtDNA) is a small DNA able to transcribe only 13 proteins so the main regulators of mitochondria homeostasis and its biogenesis are transcribed by nucleus DNA. Mitochondria biogenesis is tightly regulated by a nucleus–mitochondria signaling pathway initiated by peroxisome proliferator-activated receptor c coactivator-1a (PGC1, also known by PGC-1a and PPARGC1A). PGC1, encoded by PPARGC1A gene, is activated by environmental signals, and this in turn targets other specific transcription factors, namely, nuclear respiratory factors (NRF1/2) [35,36]. NRF1/2 are key transcription factors that regulates the expression of a number of nuclear-encoded mitochondria proteins, including mitochondrial transcription factor A (TFAM), mitochondria transporters outer membrane, cytochrome oxidase IV and cytochrome c [35–37]. TFAM translocation to the mitochondria is

749

essential to initiate mtDNA transcription and replication, key process in mitochondria biogenesis [38]. Apart from mitochondria biogenesis, PGC1 plays a role in lipid metabolism through the regulation of peroxisome proliferator-activated receptor c (PPARc) [35]. The PGC1 is regulated at the level of mRNA and protein activity in response to a variety of signaling pathways involved in cellular growth, differentiation, and energy metabolism [35]. The myocyte enhancer factor 2 (MEF2) transcription factor is a key regulator of muscle development, and one of the main regulators of PGC1 transcription. Studies well demonstrate that the PGC1 promoter area contains two MEF2-binding sites that mediate PGC1 transcriptional activation [39] Additionally, PGC1 expression per se is also regulated by PGC1 via its interaction with MEF2 on its own promoter in a feed-forward regulatory loop [40]. PGC1 seem to be activity is regulated by posttranslational modifications. Phosphorylation, mediated by 50 AMP-activated protein kinase (AMPK), and deacetylation by SIRT1 [35,41,42], seem to activate PGC1. On the other hand small ubiquitin-like modifier (SUMOylation) might attenuate PGC1 activity [43]. Therefore, once active PGC1 enhances the expression of its target genes as well as PGC1 itself. Down-regulation of PGC1 has been implicated in the development of skeletal muscle insulin resistance [44,45]. It has been reported that PGC1 ‘‘knockout’’ mouse models generally present insulin resistant or glucose intolerant phenotypes [46,47]. Indeed, PGC1 expression is decreases in skeletal muscle of diabetic patients compared to non-diabetic [45]. Accordingly, genetically and pharmacologically manipulation of PGC1 has shown to improve mitochondria function, increase mitochondria density, prevent insulin resistance and ameliorate glucose homeostasis [48,49]. However the effect of diabetes on PGC1 seems to be tissue dependent as it expression has shown to increase in organs, like retina, [50]. Therefore manipulation of PGC1 in skeletal muscle represents an exciting target to improve skeletal muscle glucose uptake and avoid/ delay the incidence of diabetes. Epigenetic modifications, PGC1 and diabetes Epigenetic modifications represent heritable changes in gene expression or cellular phenotype, caused by mechanisms other than changes in the underlying DNA sequence. Recent studies have shown that epigenetic modifications play a major role in many acquired chronic diseases, as type 2 diabetes, whereas small changes in the epigenome can change cell phenotype leading to the manifestation of the disease [50,51]. Three major epigenetic modifications known to regulate gene expression are DNA methylation, histone modifications and non-coding RNA activity (mi-RNA) [52,53]. Since little effort was taken to verify the role of mi-RNA on PGC1 pathway, this modification will not be discussed here. DNA methylation, addition of a methyl group on position 5 of cytosine of the cluster of CpG island (promoter or regulatory area of most of genes), is typically associated with transcription repression. DNA methylation brings the unintended reversible changes brought up by the environmental exposure or other life style, like physical exercise or food behavior. Cytosine 5 methylation generates 5-methylcytosine (5mC) in a reaction catalyzed by DNA (cytosine-5) methyltransferases (Dnmts) and the conversion of 5mC to 5-hydroxymethylcytosine (5hmC), a more stable modification, by Ten-eleven-translocation enzymes (TETs) [53]. Gene expression is also dictated by changes in chromatin (the structure composted by DNA and histones). DNA winds on histones and this shape gives structure to the genome and among the 4-histone proteins, histone 2A and B (H2A and H2B) and H3 and H4 form a tetrameric structure, the nucleosome. Despite of the sophisticated arranging between DNA and histone, these proteins remain susceptible to posttranslational modification, and the best-charac-

750

J.M. Santos et al. / Medical Hypotheses 82 (2014) 748–753

terized modifications are acetylation and methylation [54]. These modifications alter chromatin structure affecting the binding of the transcription factor at the gene modifying its expression. Acetylation is usually associated with gene activation since this process ‘‘relaxes’’ the chromatin allowing recruitment and binding of transcription factors and RNA polymerase [55,56]. This process is mediated by histone acetyltransferase (HATs), that add acetyl group to the histone, and by histone deacetylases (HDACs) that removes the acetyl group. Methylation of histones, on the other hand, shows a greater variability as lysine (K) can be mono-, di or tri- methylation and that adding with its location at the histone could results either activation or repression. Histone H3 lysine 4 methylation (H3K4me) is typically associated with gene activation and histone H3 lysine 9 mono-methylation (H3K9me) share the same pattern to K4, ‘‘activation’’; however, H3K9 di- and tri-methylation are generally associated with gene repression. In addition to these modifications, there are several other lysines, including H3K27, H3K36, and H3K79 that leads to altered gene expression [51,52,55]. Although large number of research suggesting epigenetic modifications as a factor that contribute to the development of diabetes type 2 there are a limited number of studies that have examined epigenetic changes in target tissues as skeletal muscle. In pancreatic islets studies have suggested that DNA hypermethylation on PGC1 promoter area might underlies decrease in insulin secretion since its significant increase in patients with diabetes type 2 compared with healthy control subjects [53]. In addition to pancreas increase in DNA methylation was linked to insulin resistance in liver [57] and heart [58]. Based on these results could be likely to presume that methylation on PGC1 promoter could also triggers the decrease on PGC1 protein in skeletal muscle observed in diabetes type 2 patients; however, only in this decade studies were carried out to address this issue and the few conclusions are not always constant. Increase in PGC1 methylation concomitant with reduction of mitochondria content was detected in skeletal muscle of type 2 diabetes humans, and the authors of this study suggested that the increased fatty-acid concentration induced methylation of PGC1 at the promoter via activation of DNMT3[59]. Accordingly, high-fat overfeeding diet offered to low-birth weight individuals (a risk factor for type 2 diabetes) induced, in a reversible manner, increase in PGC1 methylation in skeletal muscle [60]. In healthy humans 4 days of bed rest increased genes associated with insulin resistance and the DNA methylation of PGC1 [61]. Nevertheless, no significant difference was observed in PGC1 methylation between diabetic type 2 and non-diabetic twins [62], contradicting the idea that environmental changes induce decrease in PGC1 due on DNA methylation in diabetes. Therefore, the mechanism by which DNA methylation is involved into changes in PGC1 expression in diabetes requires more elucidation.

As DNA methylation, chromatin modifications are also sensitive to environmental and nutritional stimuli and that seem to affect mitochondria through PGC1 expression. Studies on skeletal muscle and neurons have suggested that class I and class II histone deacetylase (HDAC) proteins play an essential role at transcriptional repression of MEF2, the main PGC1 upstream regulator [39,63]. In addition to prevent the acetylation on PGC1 promoter area HDACs form a complex with MEF2 inhibiting its binding to PGC1 promoter. Moreover, it has been shown that pharmacological inhibition of HDAC up-regulated PGC1 and its downstream regulators. Indeed, in obese and insulin resistant animals it was observed that inhibition of class I HDAC reduces body weight, increases energy expenditure, and enhances insulin sensitivity [52]. These results imply that HDAC inhibitors might be useful in conditions associated with mitochondria dysfunction, such as type 2 diabetes. In summary environment seem to contribute to histone modification and that decreased PGC1 inducing mitochondria dysfunction leading to increase in lipid metabolites and further insulin resistance (Fig. 1).

Exercise, PGC1 and diabetes For more than 20 years studies have demonstrated the benefits of exercise and muscle contraction on improving insulin sensitivity in rodents and humans [6,11,14,64]. It is also well known that acute muscle contraction increases glucose uptake by activating GLUT4 translocation in a pathway partial independent to insulin cascade. But, comparing to insulin pathway, less is known about the regulation of contraction-stimulated glucose uptake. The potential mediators of exercise-induced glucose uptake include: calcium/calmodulin-dependent kinase (CaMK) and conventional protein kinase C (cPKC) activated by the Ca2+ and diacylglycerol elicit; AMPK activated by changes on energetic status; paracrine stimulus as nitric oxide (NO), and endocrine stimuli (reviewed by Santos et al. [6] and Jessen and Goodyear [11]). It is more likely that more than one regulator is involved together in the increase of skeletal muscle glucose uptake during contraction/exercise. The pathway activated by exercise/contraction seems to converge at insulin pathway by activating AS160 and aPKC [6]. Studies have shown that the increase in TAG and lipid metabolites impair the ability of insulin to stimulate glucose uptake and not contraction or exercise [40,65]; therefore, these results highlight the importance of these stimulus (contraction and exercise) as a therapeutic application for insulin resistant patients. Since the skeletal muscle is a highly plastic tissue the adaptation induced by aerobic exercise is also eminently effects against the development of metabolic disease, and for diabetes such modifications could improve its ability to uptake glucose by insulin in rest

Fig. 1. The effect of epigenetic modifications of PGC1 in at skeletal muscle and the development of type 2 diabetes. Changes on behaviors such as increase in high caloric food intake and physical inactive seem to increase in histone deacetylases (HDACs) and induce epigenetic modification, as histone modification (Ace- acetylation, Metmethylation) in skeletal muscle. Once histone is modified that might impairs the binding of myocyte enhancer factor 2 (MEF2) at peroxisome proliferator-activated receptor c coactivator-1a (PGC1) promoter area. Down-regulation of PGC1 induces decrease in mitochondria biogenesis and lipid metabolism leading to accumulation of lipid intermediate and triacylglycerol (TAG) in the sarcoplam, and that contribute to insulin resistance and further to the development of type 2 diabetes.

J.M. Santos et al. / Medical Hypotheses 82 (2014) 748–753

condition [8,40]. These ‘‘adjustments’’ on muscle phenotype could increment the capacity of muscle to increase glucose uptake by two ways: (i) augmenting of GLUT4 expression; (ii) attenuating elements that impair insulin stimulus through the increase of capacity of fatty acid beta-oxidation [42,66]. Importantly, PGC1 plays a key role on both. Initially Michael et al. has demonstrated in culture of myocytes that PCG1 co-activate the increase in GLUT4 expression via MEF2C binding to GLUT4 promoter area [67]. Follows, Baar et al. (2002) demonstrated that five bouts of exercise increased PGC1 and its downstream regulators that mediate mitochondria biogenesis, as NRF1, and also increase GLUT4 [68]. This idea was further corroborate in healthy humans after 4 months of aerobic exercise [69] or 2 weeks of low-volume high-intensity exercise [70], and in mice after voluntary wheel running [71]. In agreement pharmacological activation of PGC1, via AMPK and SIRT1, confirmed the effect of PGC1 on increased GLUT4 expression and on mitochondria biogenesis [72]. In addition, Potthoff et al. demonstrated in rodents that voluntary exercise increases the activity of MEF2 the upstream regulator of PGC1, and MEF2 overexpression increases the oxidative capacities and improve the exercise performance [73]. However, studies with genetic manipulation of PGC1 are not always in agreement with this idea. Miura et al.’s observed a decrease on GLUT4 mRNA and increase on mitochondria biogenesis in skeletal muscle of mice with PGC1 overexpression [74]. On the other hand, Benton et al. demonstrated in skeletal muscle of obese and lean Zucker, that two weeks after tranfection of PGC1 (which represented 25% of protein increment) increased GLUT4, improved lipid metabolism and insulin sensitivity [75]. This discrepancy could be explained by the fact that in Miura et al. study transgenic animals had an enhanced mitochondria biogenesis from the birth and that could leads to increased capacity of fatty acid oxidation and that could affect on glucose metabolism involving GLUT4 expression [74]. Altogether, these results suggest that exercise improve fatty acid oxidation, by increasing mitochondria biogenesis, and increase GLUT4 via increased expression and activity of PGC1 in skeletal muscle. Importantly, studies suggest that the beneficial effect of PGC1 is not abolished in obese and insulin resistant subjects.

Exercise, epigenetic modifications and PGC1 As mentioned previously, aerobic exercise induces skeletal muscle adaptations and alterations in gene and protein expression contribute to these adaptations [71,72]. The exact molecular mechanisms that mediate aerobic exercise-induced gene expression have not been fully elucidated but it is tempting to speculate that,

751

as happen in disease conditions, epigenetic modifications could be underlying the adaptation induced by aerobic exercise. Few studies have been carried out to determinate the role of exercise on DNA methylation in skeletal muscle. In an elegant study, Barrès et al. well demonstrated in vivo (humans) and ex-vivo (mice) that exercise and contraction, respectively, induces decrease on whole genome methylation. Importantly in this study the authors showed that DNA methylation at PGC1, MEF2, PPARc and at TFAM decreases immediately after exercise/contraction, and the decrease in PGC1 DNA methylation promoted increase in its gene expression 3 h after exercise [76]. This study suggests that acute exercise increases PGC1 expression via inhibition of the DNA methylation at its promoter area; however, further studies with different exercise protocol are required to be carried out to confirm this hypothesis. Keeping the idea that exercise induces epigenetic modification a number of researchers have verified its effect on chromatin structure. McGee et al. demonstrated that after a bout of exercise global histone 3 acetylation at lysine 9 and 14, a modification associated with transcriptional initiation, was unchanged, but at lysine 36, a site associated with transcriptional elongation, was increased [77]. Abundance of class IIa HDACs (HDAC5), were shown to be reduced in human skeletal muscle after a single bout of exercise, and HDAC5 ubiquitination, modification that labels protein for degradation, appears to mediate this process [78]. Moreover, it has been shown that overexpression of HDAC5 attenuated skeletal muscle adaptation to exercise training, and it was suggested that such effect was mediated by PGC1; however this conclusion was doubtful since in this study PGC1 was not measured [73]. In addition HDAC5 seem to interact with MEF2 resulting in inhibition of GLUT4 that reduces its expression at rest [79]. Furthermore, after acute exercise, AMPK was shown to phosphorylate HDAC5, causing its dissociation from MEF2 allowing its transcription factors to bind to the promoter area of its downstream regulator genes [79,80]. Moreover, studies demonstrated that CaMK, via Ca2+ could also mediate exercise-induced MEF2 activity. In analysis of skeletal muscle after two bouts of aerobic exercise, it was verified that CaMK was increased as well as the binding of MEF2 at GLUT4 promoter area, and that exercise effect was diminished by CaMK inhibitor [81]. Altogether its possible to suggest that the class HDAC5 can regulate PGC1 by repressing MEF2 transcription and removing acetyl groups from histone and by inhibiting MEF2, and that seem to inhibit histone acetylation at PGC1 promoter and decreases its transcription. In addition, its possible to propose that exercise could inhibit HDAC5 through AMPK and CaMK activation and that could be responsible to increase on PGC1 expression in skeletal muscle. However, no further study was performed to verify the changes in PGC1 and

Fig. 2. The role of aerobic exercise in histone modification and the expression of PGC1 in type 2 diabetes. Aerobic exercise might inhibits histone deacetylases (HDACs) that accounts to increase in histone acetylation and that could this facilitates the recruitment of myocyte enhancer factor 2 (MEF2) at peroxisome proliferator-activated receptor c coactivator-1a (PGC1) promoter area increasing its expression. SIRT1, 50 AMP-activated protein kinase (AMPK) and calcium/calmodulin-dependent kinase (CaMK), increased by exercise, activates PGC1. Once active PGC1 initiates mitochondria biogenesis pathway and increases GLUT4 expression, and that could improve insulin sensitivity and glucose uptake in skeletal muscle and further impairs the development of type 2 diabetes.

752

J.M. Santos et al. / Medical Hypotheses 82 (2014) 748–753

mitochondria biogenesis observed after aerobic exercise is due histone modification.

Conclusion and hypothesis Mitochondria dysfunction seems to play a critical role in accumulation of intramuscular fatty acid metabolites, and that is known to impair insulin-signaling pathway in skeletal muscle. PGC1, master regulator of mitochondria homeostasis, is down-regulated in insulin resistant skeletal muscle, and modification of histone resultant from increase in high caloric food intake and physical inactive appears to underlie this decrease. Aerobic exercise increases PGC1 and that appears to improve mitochondria function and density, and enhance GLUT4 expression that altogether ameliorates insulin resistance and increase glucose uptake in skeletal muscle. Moreover, aerobic exercise appears to contribute to epigenetic modification by HDAC inhibition. Therefore, based on the studies discussed above we hypothesize that environmental changes induce histones modifications in skeletal muscles and that affect PGC1 expression and further leads to mitochondria dysfunction. Once mitochondria are dysfunctional skeletal muscle become insulin resistant via increase in lipid metabolites and that leads to type 2 diabetes. Furthermore, we believe that aerobic exercise reverts histone modifications at PGC1 promoter and that facilitates the recruitment MEF2 increasing PGC1 expression. Increased PGC1 could contribute to the improvement of mitochondria biogenesis and GLUT4 expression adding to increase of insulin sensitivity and glucose uptake in skeletal muscle delaying/inhibiting the development of type 2 diabetes (Fig. 2).

Conflict of interest None declared. References [1] Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87:4–14. [2] Chan J, Malik V, Jia W, Kadowaki T, Yajnik CS, Yoon KH, et al. Diabetes in Asia. JAMA 2009;301:2129–40. [3] American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2012;35(Suppl. 1):S64–71. [4] Viana LV, Leitão CB, Kramer CK, Zucatti ATN, Jezini DL, Felício J, et al. Poor glycaemic control in Brazilian patients with type 2 diabetes attending the public healthcare system: a cross-sectional study. BMJ Open 2013;3:e003336. [5] Chou C, Cotch MF. Prevalence of nonrefractive visual. JAMA 2012;308:2361–8. [6] Santos JM, Ribeiro SB, Gaya AR, Appell H-J, Duarte JA. Skeletal muscle pathways of contraction-enhanced glucose uptake. Int J Sports Med 2008;29:785–94. [7] Santos JM, Tewari S, Goldberg AFX, Kowluru RA. Mitochondria biogenesis and the development of diabetic retinopathy. Free Radic Biol Med 2011;51:1849–60. [8] Dos Santos JM, Benite-Ribeiro SA, Queiroz G, Duarte JA. The effect of age on glucose uptake and GLUT1 and GLUT4 expression in rat skeletal muscle. Cell Biochem Funct 2012;30:191–7. [9] Karylowski O, Zeigerer A, Cohen A, Mcgraw TE. GLUT4 is retained by an intracellular cycle of vesicle formation and fusion with endosomes. Mol Biol Cell 2004;15:870–82. [10] Moller D. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 2001;414:821–7. [11] Jessen N, Goodyear LJ. Contraction signaling to glucose transport in skeletal muscle. J Appl Physiol 2005;99:330–7. [12] Mu J, Brozinick JT, Valladares O, Bucan M, Birnbaum MJ. A role for AMPactivated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 2001;7:1085–94. [13] Musi N, Fujii N, Hirshman MF, Ekberg I, Fro S, Ljungqvist O, et al. AMPactivated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes 2001;50:921–7. [14] Hayashi T, Wojtaszewski JFP, Goodyear LJ. Exercise regulation of glucose transport in skeletal muscle. Am J Physiol Endocrinol Metab 1997;273:E1039–51. [15] Leng Y, Steiler TL, Zierath JR. Mitogen-activated protein kinase signaling in skeletal muscle from lean and ob/ob mice. Diabetes 2004;53:1436–44.

[16] Tanti JF, Grillo S, Grémeaux T, Coffer PJ, Van Obberghen E, Le Marchand-Brustel Y. Potential role of protein kinase B in glucose transporter 4 translocation in adipocytes. Endocrinology 1997;138:2005–10. [17] Wang Q, Somwar R, Bilan PJ, Liu Z, Jin J, Woodgett JR, et al. Protein kinase B/Akt participates in GLUT4 translocation by insulin in L6 myoblasts. Mol Cell Biol 1999;19:4008–18. [18] Imamura T, Huang J, Usui I, Satoh H, Bever J, Olefsky JM. Involves protein kinase C-k-mediated functional coupling between Rab4 and the motor protein kinesin insulin-induced GLUT4 translocation involves protein kinase C-kmediated functional coupling between Rab4 and the motor protein kinesin. Mol Cell Biol 2003;23:4892–900. [19] Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J 2001;15:2099–111. [20] Vollenweider P, Me B, Nicod P. Activation in myotubes from obese patients with impaired glucose tolerance. Diabetes 2002;51:1052–9. [21] Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C, et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 1997;46:983–8. [22] Krssak M, Petersen KF, Dresner A, Dipietro L, Vogel SM, Rothman DL, et al. Rapid communication Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans : a 1 H NMR spectroscopy study. Diabetologia 1999;42:113–6. [23] Kraegen EW, Clark PW, Jenkins AB, Daley EA, Chisholm DJ, Storlien LH. Development of muscle insulin resistance after liver insulin resistance in highfat-fed rats. Diabetes 1991;40:1397–403. [24] Kelley DE, Mokan M, Simoneau JA, Mandarino LJ. Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest 1993;92:91–8. [25] Boden G, Chen X, Ruiz J, White JV, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 1994;93:2438–46. [26] Jucker BM. 13C and 31P NMR studies on the effects of increased plasma free fatty acids on intramuscular glucose metabolism in the awake rat. J Biol Chem 1997;272:10464–73. [27] Guo Z. Intramyocellular lipid kinetics and insulin resistance. Lipids Health Dis 2007;6:18. [28] Aguirre V. The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J Biol Chem 2000;275:9047–54. [29] Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 2002;277:48115–21. [30] Moeschel K, Beck A, Weigert C, Lammers R, Kalbacher H, Voelter W, et al. Protein kinase C-zeta-induced phosphorylation of Ser318 in insulin receptor substrate-1 (IRS-1) attenuates the interaction with the insulin receptor and the tyrosine phosphorylation of IRS-1. J Biol Chem 2004;279:25157–63. [31] Rieusset J. Mitochondria and endoplasmic reticulum: mitochondriaendoplasmic reticulum interplay in type 2 diabetes pathophysiology. Int J Biochem Cell Biol 2011;43:1257–62. [32] Yan J, Feng Z, Liu J, Shen W, Wang Y, Wertz K, et al. Enhanced autophagy plays a cardinal role in mitochondrial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rats: ameliorating effects of ()-epigallocatechin-3-gallate. J Nutr Biochem 2012;23:716–24. [33] Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and Type 2 diabetes. Mol Cell 2008;9:367–77. [34] Holloszy JO. Skeletal muscle ‘‘mitochondrial deficiency’’ does not mediate insulin resistance. Am J Clin Nutr 2009;89:463S–6S. [35] Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 2008;88:611–38. [36] Evans MJ, Scarpullas C. Interaction of nuclear factors with multiple sites in the somatic cytochrome c promoter. J Biol Chem 1989;264:14361–8. [37] Piantadosi CA, Suliman HB. Mitochondrial transcription factor A induction by redox activation of nuclear respiratory factor 1. J Biol Chem 2006;281:324–33. [38] Ohgaki K, Kanki T, Fukuoh A, Kurisaki H, Aoki Y, Ikeuchi M, et al. The Cterminal tail of mitochondrial transcription factor a markedly strengthens its general binding to DNA. J Biochem 2007;141:201–11. [39] Czubryt MP, McAnally J, Fishman GI, Olson EN. Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and mitochondrial function by MEF2 and HDAC5. Proc Natl Acad Sci USA 2003;100:1711–6. [40] Lira VA, Benton CR, Yan Z, Bonen A. PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab 2010;299:E145–61. [41] Ringholm S, Olesen J, Pedersen JT, Brandt CT, Halling JF, Hellsten Y, et al. Effect of lifelong resveratrol supplementation and exercise training on skeletal muscle oxidative capacity in aging mice; impact of PGC-1a. Exp Gerontol 2013;48:1311–8. [42] Scarpulla RC. Metabolic control of mitochondial biogenesis trough the PCC-1 family regulatory network. Biochim Biophys Acta 2011;1813:1269–78. [43] Rytinki MM, Palvimo JJ. SUMOylation attenuates the function of PGC-1alpha. J Biol Chem 2009;284:26184–93. [44] Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003;34:267–73. [45] Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance

J.M. Santos et al. / Medical Hypotheses 82 (2014) 748–753

[46]

[47]

[48]

[49]

[50] [51]

[52]

[53] [54]

[55] [56] [57]

[58]

[59]

[60]

[61]

[62]

[63]

and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci USA 2003;100:8466–71. Lelliott CJ, Medina-gomez G, Petrovic N, Kis A, Feldmann HM, Bjursell M, et al. Ablation of PGC-1 b results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol 2006;4:e369. Sonoda J, Mehl IR, Chong L-W, Nofsinger RR, Evans RM. PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc Natl Acad Sci USA 2007;104:5223–8. Jackson JR, Ryan MJ, Alway SE. Long-term supplementation with resveratrol alleviates oxidative stress but does not attenuate sarcopenia in aged mice. J Gerontol A Biol Sci Med Sci 2011;66:751–64. Muoio DM, Koves TR. Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1 alpha: implications for metabolic disease. Appl Physiol Nutr Metab 2007;32:874–83. Santos JM, Mohammad G, Zhong Q, Kowluru RA. Diabetic retinopathy, superoxide damage and antioxidants. Curr Pharm Biotechnol 2011;12:352–61. Zhong Q, Kowluru RA. Regulation of matrix metalloproteinase-9 by epigenetic modifications and the development of diabetic retinopathy. Diabetes 2013;62:2559–68. Galmozzi A, Mitro N, Ferrari A, Gers E, Gilardi F, Godio C, et al. Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue. Diabetes 2013;62:732–42. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010;28:1057–68. Santos JM, Kowluru RA. Impaired transport of mitochondrial transcription factor A (TFAM) and the metabolic memory phenomenon associated with the progression of diabetic retinopathy. Diabetes Metab Res Rev 2013;29:204–13. Bird A. Perceptions of epigenetics. Nature 2007;447:396–8. Kowluru RA, Santos JM, Mishra M. Epigenetic modifications and diabetic retinopathy. Biomed Res Int 2013 [epub ahead of print]. Pooya S, Blaise S, Moreno Garcia M, Giudicelli J, Alberto JM, Guéant-Rodriguez RM, et al. Methyl donor deficiency impairs fatty acid oxidation through PGC1a hypomethylation and decreased ER-a, ERR-a, and HNF-4a in the rat liver. J Hepatol 2012;57:344–51. Garcia MM, Guéant-Rodriguez RM, Pooya S, Brachet P, Alberto JM, Jeannesson E, et al. Methyl donor deficiency induces cardiomyopathy through altered methylation/acetylation of PGC-1a by PRMT1 and SIRT1. J Pathol 2011;225:324–35. Barrès R, Osler ME, Yan J, Rune A, Fritz T, Caidahl K, et al. Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab 2009;10:189–98. Brøns C, Jacobsen S, Nilsson E, Rönn T, Jensen CB, Storgaard H, et al. Deoxyribonucleic acid methylation and gene expression of PPARGC1A in human muscle is influenced by high-fat overfeeding in a birth-weightdependent manner. J Clin Endocrinol Metab 2010;95:3048–56. Alibegovic AC, Sonne MP, Højbjerre L, Bork-Jensen J, Jacobsen S, Nilsson E, et al. Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men. Am J Physiol Endocrinol Metab 2010;299:E752–63. Ribel-Madsen R, Fraga MF, Jacobsen S, Bork-Jensen J, Lara E, Calvanese V, et al. Genome-wide analysis of DNA methylation differences in muscle and fat from monozygotic twins discordant for type 2 diabetes. PLoS One 2012;7:e51302. Raichur S, Teh SH, Ohwaki K, Gaur V, Long YC, Hargreaves M, et al. Histone deacetylase 5 regulates glucose uptake and insulin action in muscle cells. J Mol Endocrinol 2012;49:203–11.

753

[64] Benite-Ribeiro SA, Dos Santos JM, Duarte JAR. Moderate physical exercise attenuates the alterations of feeding behaviour induced by social stress in female rats. Cell Biochem Funct 2014;32:142–9. [65] Wheatley CM, Rattigan S, Richards SM, Barrett EJ, Clark MG. Skeletal muscle contraction stimulates capillary recruitment and glucose uptake in insulinresistant obese Zucker rats. Am J Physiol Endocrinol Metab 2004;287:E804–9. [66] Wright DC. Mechanisms of calcium-induced mitochondrial biogenesis and GLUT4 synthesis. Appl Physiol Nutr Metab 2007;32:840–5. [67] Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G, Lehman JJ, et al. Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci USA 2001;98:3820–5. [68] Baar K, Wende AR, Jones TE, Marison M, Nolte LA, et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB 2002;16:1879–86. [69] Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, Coenen-Schimke JM, et al. Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes 2003;52:1888–96. [70] Little JP, Safdar A, Wilkin GP, Tarnopolsky MA, Gibala MJ. A practical model of low-volume high-intensity interval training induces mitochondrial biogenesis in human skeletal muscle: potential mechanisms. J Physiol 2010;588:1011–22. [71] Ikeda S, Kawamoto H, Kasaoka K, Hitomi Y, Kizaki T, Sankai Y, et al. Muscle type-specific response of PGC-1 alpha and oxidative enzymes during voluntary wheel running in mouse skeletal muscle. Acta Physiol 2006;188:217–23. [72] Leick L, Fentz J, Biensø RS, Knudsen JG, Jeppesen J, Kiens B, et al. PGC-1{alpha} is required for AICAR-induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle. Am J Physiol Endocrinol Metab 2010;299:E456–65. [73] Potthoff MJ, Wu H, Arnold MA, Shelton JM, Backs J, McAnally J, et al. Histone deacetylase degradation and MEF2 activation promote the formation of slowtwitch myofibers. J Clin Invest 2007;117:2459–67. [74] Miura S, Kai Y, Ono M, Ezaki O. Overexpression of peroxisome proliferatoractivated receptor gamma coactivator-1alpha down-regulates GLUT4 mRNA in skeletal muscles. J Biol Chem 2003;278:31385–90. [75] Benton CR, Holloway GP, Han X-X, Yoshida Y, Snook LA, Lally J, et al. Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats. Diabetologia 2010;53:2008–19. [76] Barrès R, Yan J, Egan B, Treebak JT, Rasmussen M, Fritz T, et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab 2012;15:405–11. [77] McGee SL, Fairlie E, Garnham AP, Hargreaves M. Exercise-induced histone modifications in human skeletal muscle. J Physiol 2009;15:5951–8. [78] Ntanasis-Stathopoulos J, Tzanninis JG, Philippou A, Koutsilieris M. Epigenetic regulation on gene expression induced by physical exercise. J Musculoskelet Neuronal Interact 2013;13:133–46. [79] McGee SL, Hargreaves M. Exercise and skeletal muscle glucose transporter 4 expression: molecular mechanisms. Clin Exp Pharmacol Physiol 2006;33:395–9. [80] Vissing K, Anderson JL, Harridge SDR, Sandri C, Hartkopp A, Kjaer M, et al. Gene expression of myogenic factors and phenotype-specific markers in electrically stimulated muscle of paraplegics. J Appl Physiol 2005;99:164–72. [81] Smith JAH, Kohn TA, Chetty AK, Ojuka EO. CaMK activation during exercise is required for histone hyperacetylation and MEF2A binding at the MEF2 site on the Glut4 gene. Am J Physiol Endocrinol Metab 2008;295:E698–704.