Abstract
Transcriptional factors are easily susceptible to any stimuli, including exercise. Exercise can significantly influence PGC-1 α and AMPK-SIRT1 pathway, as it is involved in the regulation of energy metabolism and mitochondrial biogenesis. Exercise is a major energy deprivation process by which many of transcription factors get tuned positively. However, how transcription factors help to boost the antioxidant defense system at cellular level is elusive. It is well known that physical exercise can induce reactive oxygen species, but how these reactive oxygen species can help to regulate multiple transcription factors during exercise is an important area to be discussed yet. This review mainly focuses on interconnecting role of PGC-1 α and AMPK-SIRT1 pathway during exercise and how these proteins are getting tuned by reactive oxygen species in exercise condition.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
There are interconnections in every cellular network in order to adapt to the external stimuli, including exercise. These interconnected networks are involved in the regulation of energy metabolism, e.g., peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α), adenosine monophosphate protein kinase (AMPK), and sirtuin (SIRT1) network. These networks respond to many stimuli, including physical exercise [12, 61]. Physical exercise is known to induce the metabolic adaptations in muscles via activating the associated transcription factors [9, 14]. However, molecular-based adaptation in response to exercise is unequivocal. Reactive oxygen species (ROS) production during exercise can induce many transcription coactivators and factors positively, but its coordinated mechanism is not well established. Among these transcription factors, PGC-1 α plays a central role in mitochondrial biogenesis and antioxidants boosting via several signaling kinases, including AMPK and p38. This review discusses the overview of PGC-1 α and AMPK-SIRT1 mechanisms by which how these proteins are getting regulated itself during exercise and how the ROS molecules interlink these proteins during exercise; we searched many articles published up to 2016 in PubMed, Medline, and Embase for addressing the role of ROS-mediated PGC-1 alpha and AMPK-SIRT1 during exercise.
ROS are a family of molecules that are continuously generated, transformed, and utilized for various pathophysiological processes in all aerobic living organisms [22]. These ROS induce oxidative stress and damage many cellular and subcellular systems. However, recent studies show that ROS serve as multi-connecting factors in the signaling mechanism particularly exercise-mediated mechanism, but increased ROS production can perturb the exercise-mediated signaling and thus lead to reduced muscle activity during exercise. Studies have shown that various organelles within the cell can generate ROS such as mitochondria, sarcoplasmic reticulum and peroxisomes in exercise condition [15, 21, 64]. In addition, various enzymatic systems, including oxidases and oxygenases produce ROS. However, the random production of ROS impedes to know the exact source during physical activity.
PGC-1 alpha is a transcriptional coactivator that interacts with many other transcription factors in different biological responses, including mitochondrial biogenesis and glucose/fatty acid metabolism [35]. PGC-1 alpha is a first member of PGC family expressed highly where mitochondria are abundant and oxidative metabolism is active, including brown adipose tissue, the heart, and skeletal muscle. PGC-1 alpha expression is also found in the brain, kidney, and at a very low level in white adipose tissue [62]. PGC-1 alpha is composed of an N-terminal region, a middle region, and a C-terminal region. The N-terminal region is key to control the interaction of PGC-1 alpha with other transcription factors such as nuclear respiratory factor 1 (NRF-1), myocyte enhancer factor-2C (MEF2C), and forkhead box protein O1 (FOXO1) [42, 63]. The C-terminal region controls the stability of PGC-1 alpha, as it possesses RNA recognition motifs.
AMPK is a fuel-sensing enzyme found in all mammals and unicellular organisms. Its activation is regulated by the ratio of adenosine monophosphate and adenosine triphosphate (AMP–ATP) due to stresses which deprive the consumption of ATP in relation with increased AMP (e.g., muscle contraction). The enzyme is a heterotrimeric structure composed of one catalytic (α) and two regulatory (β,γ) subunits. These subunits have further two or more isoforms, and their presence varies among different species and types of tissues, but their expression is necessary for full AMPK activity [12, 13, 26, 27]. Under lowered intracellular ATP levels, AMP binds to the γ subunit of AMPK and further causes the conformational changes in the heterotrimeric and phosphorylate the 172 threonine residue of the AMPK α subunit. This 172 threonine phosphorylation is required for catalytic activity. Recent evidence has found that liver kinase B1 (LKB1) is a major upstream enzyme that phosphorylates the 172 threonine residue of the AMPK α subunit in the skeletal muscle [40, 41].
Sirtuins have received significant interest for its regulatory role in the metabolism in response to physiological changes. Sirtuins family is composed of seven proteins (SIRT1–SIRT7), and they vary in source tissues, enzymatic activities, and targets. Sirt1 is the most studied member of the Sirtuins family, present mainly not only in nucleus but also in cytoplasm. It was initially found to deacetylate the histones, but later it was shown that Sirt1 deacetylates other proteins as well [29, 30, 45, 55]. Sirt1 is known to regulate more than 40 protein targets through its deacetylase activity and also is an important regulator of muscle differentiation and metabolism [28, 56]. It has been purported as a central regulator of the mitochondrial biogenesis in the skeletal muscle, as it deacetylates PGC-1 alpha.
Role of nitric oxide in exercise
In the recent decades, nitric oxide (NO) research has gained more importance in exercise physiology. This labile molecule plays an important role in regulating vasodilation, muscle contractility, and mitochondrial respiration. It is synthesized by nitric oxide synthase (NOS)-dependent mechanism in endogenous systems and also it can be increased by dietary supplements sources such as glycin propionyl-l-carnitine. In relation with exercise, NO is increased due to shear stress on vessel walls during exercise and thus improves the oxygen delivery and nutrients to muscles, resulting in increased muscle strength and recovery mechanism. Prolonged exercise increases the NO production, resulting in vasodilation in the heart and skeletal muscles. However, strenuous exercise increases the chances of superoxide production, thereby decreasing the bioavailability of NO, as superoxide combines with NO to produce peroxynitrite—a potent cellular damager. In this scenario, we mainly review about PGC-1 alpha and AMPK, and how NO can act with AMPK synergistically to upregulate the PGC-1 alpha. Lira et al. [48, 49] reported that NO and AMPK cooperatively regulate the PGC-1 alpha and stimulate the mitochondrial biogenesis in the skeletal muscle cells. However, this mechanism is still illusive in exercise biology.
PGC-1 alpha role in exercise
The coordinated function of PGC-1 α with other transcriptional factors in the cellular process augments the interest to reveal its role in exercise biology. PGC-1 α is a key regulator of exercise-induced phenotype adaptation in the muscles [49].Overexpression of PGC-1 α increases the mitochondrial biogenesis, thus increasing the capacity of oxidative fiber in the muscles. PGC-1 α regulates many transcriptional factors, including mitochondrial transcription factor A (TFAM) and nuclear respiratory factors (NRF-1 and NRF-2) [18, 63]. Furthermore, PGC-1 α is a direct binding site for MEF2, which regulates the muscles fiber type, particularly slow type, resulting in increased endurance activity [18, 60]. A single bout of exercise can induce increased expression of PGC-1 α; however, its level reverts to normal when physical activity is stopped. However, chronic exercise alters the plasticity of muscle toward oxidative fiber type, resulting in increased expression of PGC-1 α [59]. Fiber-type switching toward the oxidative type by PGC-1 α is characterized by increased mitochondrial production, density, and oxidative metabolism [46]. Conversely, glycolytic fiber of muscles decreased the endurance activity [33]. Taken together, PGC-1 α is a key mediator of several cellular processes required for endurance capacity.
Role of ROS/RNS-dependent PGC-1 α and antioxidants in exercise
The prematurely donated electrons to oxygen in the electron transport chain become reactive oxygen (superoxide) anions in the mitochondria. These superoxide radicals are further dismutated into H2O2 by superoxide dismutase (SOD). Hydrogen peroxide can be reduced to water by catalase (CAT) and glutathione peroxidase (GPx); alternatively, it becomes OH radicals via Fenton reaction. These superoxide and OH radicals have a negative impact on cellular proteins and lipids through oxidation, resulting in cellular damage that is associated with a wide variety of diseases including degenerative disorders. However, ROS have been linked with several essential cellular signaling processes of growth regulation, differentiation, proliferation, and apoptosis. Mitochondrial biogenesis is an important process by which energy depletion can be saturated during exercise. ROS have been shown to regulate many transcriptional coactivators that are required for mitochondrial biogenesis, including PGC-1 α.
It is well known that endurance training can increase the activity of PGC-1 α in the skeletal muscle, but its activity depends, at least in part, on ROS mechanism [5, 67, 68]. For example, PGC-1 α is activated through phosphorylation by p38 MAPK along with nuclear factor kappa-light-chain-enhancer of activated B (NF-κB), but both are known to be activated by ROS in the muscles; also Ca2+ signaling may help to autoregulate PGC-1 α through MEF2, which is an important regulator of muscle cell differentiation and development [32, 39, 52], and in this case also ROS play a crucial role in the regulation of Ca2+ signaling. Although PGC-1 α represents the master regulator of mitochondrial biogenesis, it is an upstream activator of mitochondrial metabolism in the muscles, influencing the amount of ROS production. However, studies proposed that PGC-1 α expression is regulated by ROS and thereby a potential network between PGC-1 alpha and ROS [3, 25, 66,67,68]. For example, there is a reasonable chance to increase the ROS production during exercise in the skeletal muscles, as exercise increases the activity of PGC-1 α, but PGC-1 α can consequently activate several detoxifying enzymes. St-Pierre et al. [65] reported that ectopic expression of PGC-1 alpha in muscle cells increases the expression of SOD2 and GPx1, which remove superoxide and hydrogen peroxide, and their further studies confirmed that PGC-1 α regulated these detoxifying enzymes [66,67,68] particularly in the promoter sequence of MnSOD and glutathione system [10], and thus, antioxidants and PGC-1 alpha coordinately regulate the mitochondrial system in the skeletal muscles and remove the toxic derivatives in the muscles during exercise [23]. However, depletion of antioxidants can also alter the PGC-1 α expression. Aquilano et al. [1] found that glutathione decrement due to metabolic stress in exercised condition increases the expression of PGC-1 α via p53. PGC-1 alpha can also be involved in reducing the ROS generation by increasing the expression of uncoupling proteins UCP-1 and UCP-2 which dissipates the proton gradient and reduces the mitochondrial membrane potential [53]. Conversely, ROS are involved in the regulation of PGC-1 α. For example, H2O2 regulates the expression PGC-1 α via AMPK pathway and indirectly it is involved in upregulation of PGC-1 α by lactate, a by-product of glycolytic pathway [43, 44]. Therefore, it is a multi-dependent process of PGC-1 α, antioxidants, and ROS. Ample evidence supported that muscle contraction during exercise increased the production of ROS in the form of superoxide (O2), hydrogen peroxide (H2O2), and hydroxyl (OH) radicals [10, 39, 65]. H2O2 is an important signaling molecule for muscle adaptation. However, ROS have been shown to increase the expression of PGC-1 α and metabolic adaptation in the muscles, but at what level the production of ROS could help regulate PGC-1 α during exercise needs more study. Additionally, reactive nitrogen species (RNS) play an important role in the regulation of PGC-1 α; particularly, NO increases the PGC-1 α expression via AMPK activation and Ca2+/calmodulin. Nitric oxide production is increased during physical exercise [2, 58]. Several studies have suggested the role of NO in the PGC-1 α regulation, mitochondrial biogenesis, and fiber type changes [48, 51].
Role of PGC-1 α in mitochondrial biogenesis of muscular adaptation
Muscular adaptation involves activation of many transcriptional factors and coactivators that regulate the mitochondrial biogenesis and muscle fiber type. It is believed that exercise induces the mitochondrial biogenesis by mimicking the activity of transcription factors [36, 38, 47]. This increased amount of mitochondria in the skeletal muscle can have many beneficial health effects including exercise endurance and oxidative capacity. Recent studies have proved that PGC-1 α is an important transcription coactivator that supports to activate other transcription factors (MEF), nuclear respiratory factors (NRF-1 and NRF-2) [46] and upregulate gene expression of mitochondrial biogenesis. Thus, it is a master regulator in mitochondrial biogenesis and also considered as a one of the important factors influencing muscle fiber type. Exercise like stimuli induces the PGC-1 α expression, which contributes the muscular contraction activity. This contraction activates the Ca2+ channels leading to increased amount of Ca2+ in the cytosol. This increased amount of Ca2+ stimulates the calcium/calmodulin-dependent protein kinase, which further phosphorylates the PGC-1 α. In another way, muscle contraction-mediated AMPK and p38 MAPK induces PGC-1 α expression. PGC-1 α can also regulate the homeostasis of oxidants and antioxidants by increasing the stimulation of superoxide dismutase-2, catalase, and GPx expression. Taken together, PGC-1 α plays a crucial role in response to external stimuli like exercise to increase the mitochondrial biogenesis by mimicking the many metabolic responses and transcription factors including NRF.
Interconnecting role of AMPK-SIRT1 and PGC-1 α during exercise
Significant understanding of AMPK-SIRT1 and PGC-alpha has been gained both animal and clinical models (Tables 1 and 2). AMPK regulates both anabolic and catabolic processes to balance the energy level. During exercise, AMPK is activated for energy-consuming process, as it regulates the glucose uptake and fatty acid oxidation. Several studies suggest that AMPK is involved in mitochondrial biogenesis, angiogenesis, and calorie restriction [19, 37, 70]. A single bout of exercise can activate AMPK, resulting in stimulation of many metabolic pathways and also its activation leads to mimic several signaling factors in response to muscle adaptation. Both physical exercise and physical inactivity can either activate or inactivate the AMPK pathway, but its complete activation depends on the intensity of exercise. For example, AMPK activation has been reported after an hour at 75% VO2max until exhaustion [69] and also threonine 172 phosphorylation of AMPK α2 was increased at 45% VO2max [70]. Likewise, Chen et al. [16] reported that the duration as well as the intensity and type of exercise can directly increase the AMPK activation in human muscles. In addition to physical exercise, other forms of stresses including hypoxia also increased the AMPK level in the skeletal and cultured muscles [54]. Although various signaling pathways are involved in regulating the antioxidant defense system for giving protection against ROS-mediated damage, AMPK–SIRT1 is a major signaling pathway involved in controlling different transcription coactivators and factors like PGC-1 α, FOXO1, and NF-κB that are directly linked with ROS production in order to protect muscle cells from ROS-mediated damage and inflammatory mediators, and thus it becomes an important therapeutic target to unravel the physiological role of muscle and other tissues.
As noted earlier, LKB1 is an important enzyme present in muscles and its deacetylation or phosphorylation is crucial to activate the AMPK. Recent reports suggest that silent information regulator 1 (Sirt1) is a NAD+-dependent histone/protein deacetylase, which may deacetylate the LKB1, and it leads to activate the AMPK [45]. Price et al. [61] showed that SIRT1 is required for AMPK activation in the resveratrol treatment. They reported that low-dose resveratrol induces the AMPK activation in a SIRT1-dependent manner. These collective reports suggested that AMPK activity relies on SIRT1 activity. In contrast, SIRT1 activity depends on AMPK activation but in different mechanism. For example, Fulco et al. [29] found that AMPK can activate SIRT1 in vitro through nicotinamide phosphoribosyl transferase (Nampt) which in turn activate NAD+/NADH, the substrate for SIRT-1. Interestingly, AMPK and SIRT1 mediate the PGC-1 α expression in mitochondrial biogenesis and glucose metabolism. In a recent report, AMPK phosphorylates the PGC-1 α directly [35]. However, how this happens is still elusive. AMPK-mediated SIRT1 deacetylates the PGC-l α which in turn increased activity of PGC-1 α. Canto et al. [12] showed that AMPK-dependent PGC-1 alpha activation relies on SIRT1 activation. Nemoto et al. [55] have explained the complex relationship between SIRT1, PGC-1 α, and mitochondrial function in PC12 cells. Similarly, Gerhart-Hines et al. [30] showed that SIRT1 expression is regulated by PGC-1 as ectopic expression of PGC-1 α, and also these authors were the first to demonstrate the role of SIRT1 on mitochondrial adaptation in skeletal muscle. Altogether, SIRT1, AMPK, and PGC-1 α have an imperative role to increase the mitochondrial adaptation to exercise. From these collective reports, we speculate that abnormal or overexercise can increase the amount of ROS generation in muscles and that it further causes the oxidative environment in the muscle. This increased oxidative environment may impair AMPK, SIRT1, and PGC-1 α, mediated pathways. During vigorous exercise, ATP production is increased to sustain the energy demand in the muscle. This increased intracellular ATP level causes AMP depletion as a result of decreased activity of AMPK, and this further decreases the SIRT1 activity. Reduced activity of SIRT1 may fail to deacetylate the LKB1, PGC-1 α, FOXO1, and tumor necrosis factor alpha (TNF-α), which in turn reduces the endogenous antioxidants expression, and this condition may activate the NF-κB, iNOS, and NoXs, resulting in increased amount of ROS (Fig. 1). However, this linking mechanism needs to be established more clearly.
Conclusions and future aspects
A large number of studies reveal that the transcription factors and coactivators play an important role in the positive response of ROS during exercise. Although these transcription factors help to regulate the redox system during exercise, limited evidences persist regarding PGC-1 α and AMPK-SIRT1 connection on ROS regulation and how the ROS mediate these signaling processes in response to external stimuli including exercise. Even less is known about these PGC-1 α and AMPK-SIRT1 networks from a therapeutic aspect. However, different mechanisms are involved in response to exercise. Further quantitative studies will reveal the holistic benefits of these proteins, paving way for their therapeutic applications in muscle-related pathology, as well as determining proper exercises to prevent diseases associated with these proteins.
Abbreviations
- AMP:
-
Adenosine monophosphate
- AMPK:
-
Adenosine monophosphate protein kinase
- ATP:
-
Adenosine triphosphate
- CAT:
-
Catalase
- FoxO1:
-
Forkhead box protein O1
- H2O2 :
-
Hydrogen peroxide
- iNOS:
- LKB1:
-
Liver kinase B1
- MEF:
-
Myocyte enhancer factor
- NRF-1:
-
Nuclear respiratory factor 1
- NRF-2:
-
Nuclear respiratory factor 2
- NAD+ :
-
Nicotinamide adenine dinucleotide
- NADH:
-
Nicotinamide adenine dinucleotide dehydrogenase
- Nampt:
-
Nicotinamide phosphoribosyl transferase
- NF-κB:
-
Nuclear factor kappa-light-chain-enhancer of activated B
- NoXs:
-
NADPH oxidases
- OH:
-
Hydroxyl radicals
- PGC-1 α:
-
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
- ROS/RNS:
-
Reactive oxygen species/reactive nitrogen species
- SIRT1:
-
Sirtuin
- SOD:
-
Superoxide dismutase
- TNF-α:
-
Tumor necrosis factor alpha
- TFAM:
-
Mitochondrial transcription factor A
- UCP1:
-
Uncoupling protein 1
- UCP2:
-
Uncoupling protein 2
References
Aquilano K, Baldelli S, Pagliei B, Cannata SM, Rotilio G, Ciriolo MR (2013) p53 orchestrates the PGC-1alpha-mediated antioxidant response upon mild redox and metabolic imbalance. Antioxid Redox Signal 18:386–399
Balon TW, Nadler JL (1994) Nitric oxide release is present from incubated skeletal muscle preparations. J Appl Physiol 77:2519–2521
Baldelli S, Aquilano K, Ciriolo MR (2014) PGC-1α buffers ROS-mediated removal of mitochondria during myogenesis. Cell Death Dis 6:e1515
Banks AS, Kon N, Knight C, Matsumoto M, Gutierrez-Juarez R, Rossetti L (2008) SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 8(4):333–341
Barbieri E, Sestili P (2012) Reactive oxygen species in skeletal muscle signaling. J Signal Transduct 2012:982794
Barnes BR et al (2005) Changes in exercise-induced gene expression in 5′-AMP-activated protein kinase γ3-null and γ3 R225Q transgenic mice. Diabetes 54:3484–3489
Barnes BR et al (2005) 5′-AMP-activated protein kinase regulates skeletal muscle glycogen content and ergogenics. FASEB J 19:773–779
Barnes BR et al (2004) The 5′-AMP-activated protein kinase γ3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle. J Biol Chem 279:38441–38447
Bayod S, Del Valle J, Lalanza JF et al (2012) Long-term physical exercise induces changes in sirtuin 1 pathway and oxidative parameters in adult rat tissues. Exp Gerontol 47:925–935
Bedogni B, Pani G, Colavitti R, Riccio A, Borrello S, Murphy M et al (2003) Redox regulation of cAMP-responsive element-binding protein and induction of manganous superoxide dismutase in nerve growth factor-dependent cell survival. J Biol Chem 278:16510–16519
Calvo JA, Daniels TG, Wang X, Paul A, Lin J, Spiegelman BM, Stevenson SC, Rangwala SM (2008) Muscle-specific expression of PPARγ coactivator-1α improves exercise performance and increases peak oxygen uptake. J Appl Physiol 104:1304–1312
Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L et al (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458:1056–1060
Carling D, Thornton C, Woods A, Sanders MJ (2012) AMP-activated protein kinase: new regulation, new roles? Biochem J 445:11–27
Chabi B, Ljubicic V, Menzies KJ, Huang JH, Saleem A, Hood DA (2008) Mitochondrial function and apoptotic susceptibility in aging skeletal muscle. Aging Cell 7:2–12
Cherednichenko G, Zima AV, Feng W, Schaefer S, Blatter LA, Pessah IN (2004) NADH oxidase activity of rat cardiac sarcoplasmic reticulum regulates calcium-induced calcium release. Circ Res 94(4):478–486
Chen ZP, McConell GK, Michell BJ, Snow RJ, Canny BJ, Kemp BE (2000) AMPK signaling in contracting human skeletal muscle:acetyl-CoA carboxylase and NO synthase phosphorylation. Am J Physiol Endocrine Metab 279:E1202–E1206
Chen ZP, Stephens TJ, Murthy S, Canny BJ, Hargreaves M, Witters LA, Kemp BE, McConell GK (2003) Effect of exercise intensity on skeletal muscle AMPK signaling in humans. Diabetes 52:2205–2212
Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton JM, Wu H, Zhu W, Bassel-Duby R, Williams RS (1998) A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev 12:2499–2509
Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, Ravussin E (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 4:e76
Costford SR, Bajpeyi S, Pasarica M et al (2010) Skeletal muscle NAMPT is induced by exercise in humans. Am J Physiol Endocrinol Metab 298(1):E117–E126
Davies KJ, Maguire JJ, Brooks GA, Dallman PR, Packer L (1982) Muscle mitochondrial bioenergetics, oxygen supply, and work capacity during dietary iron deficiency and repletion. Am J Phys 242(6):E418–E427
Dickinson BC, Chang CJ (2011) Chemistry and biology of reactive oxygen species in signaling or stress. Nat Chem Biol 7(8): 504–511
Finkel T (2006) Cell biology: a clean energy programme. Nature 444:151–152
Flores MB, Fernandes MF, Ropelle ER, Faria MC, Ueno M, Velloso LA, Saad MJ, Carvalheira JB (2006) Exercise improves insulin and leptin sensitivity in hypothalamus of Wistar rats. Diabetes 55:2554–2561
Fu X, Yao K, Du X, Li Y, Yang X, Yu M, Li M, Cui Q (2016) PGC-1α regulates the cell cycle through ATP and ROS in CH1 cells J Zhejiang Univ Sci B 17(2): 136–146
Fujii N, Hirshman MF, Kane EM, Ho RC, Peter LE, Seifert MM, Goodyear LJ (2005) AMP-activated protein kinase α2 activity is not essential for contraction- and hyperosmolarity-induced glucose transport in skeletal muscle. J Biol Chem 280:39033–39041
Fujii N, Jessen N, Goodyear LJ (2006) AMP-activated protein kinase and the regulation of glucose transport. Am J Physiol Endocrinol Metab 291:E867–E877
Fulco M, Schiltz RL, Iezzi S, King MT, Zhao P, Kashiwaya Y, Hoffman E, Veech RL, Sartorelli V (2003) Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol Cell 12:51–62
Fulco M, Cen Y, Zhao P, Hoffman EP, McBurney MW, Sauve AA, Sartorelli V (2008) Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell 14:661–673
Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 26:1913–1923
Gurd BJ, Yoshida Y, McFarlan JT et al (2011) Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 301(1):R67–R75
Handschin C, Rhee J, Lin J, Tarr PT, Spiegelman BM (2003) An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proc Natl Acad Sci U S A 100:7111–7116
Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur NK, Yan Z, Spiegelman BM (2007) Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1_ muscle-specific knock-out animals. J Biol Chem 282:30014–30021
Handschin C, Spiegelman BM (2008) The role of exercise and PGC1α in inflammation and chronic disease. Nature 454(7203): 463–469
Jäger S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc Natl Acad Sci U S A 104:12017–12022
Jornayvaz FR, Shulman GI (2010) Regulation of mitochondrial biogenesis. Essays Biochem 47:69–84
Joseph AM, Pilegaard H, Litvintsev A, Leick L, Hood DA (2006) Control of gene expression and mitochondrial biogenesis in the muscular adaptation to endurance exercise. Essays Biochem 42:13–29
Kelly DP, Scarpulla RC (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18:357–368
Kiningham KK, Xu Y, Daosukho C, Popova B, St Clair DK (2001) Nuclear factor kappaB-dependent mechanisms coordinate the synergistic effect of PMA and cytokines on the induction of superoxide dismutase 2. Biochem J 353:147–156
Koh HJ, Arnolds DE, Fujii N, Tran TT, Rogers MJ, Jessen N, Li Y, Liew CW, Ho RC, Hirshman MF, Kulkarni RN, Kahn CR, Goodyear LJ (2006) Skeletal muscle-selective knockout of LKB1 increases insulin sensitivity, improves glucose homeostasis, and decreases TRB3. Mol Cell Biol 26:8217–8227
Koh HJ, Brandauer J, Goodyear LJ (2008) LKB1 and AMPK and the regulation of skeletal muscle metabolism. Curr Opin Clin Nutr Metab Care 11:227–232
Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ et al (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419:316–321
Kukidome D, Nishikawa T, Sonoda K, Imoto K, Fujisawa K, Yano M, Motoshima H, Taguchi T, Matsumura T, Araki E (2006) Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 55:120–127
Hashimoto T, Hussien R, Oommen S, Gohil K, Brooks GA (2007) Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. FASEB J 21:2602–2612
Lan F, Cacicedo JM, Ruderman N, Ido Y (2008) SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 283:27628–27635
Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM (2002) Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418:797–801
Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–370
Lira VA, Soltow QA, Long JH, Betters JL, Sellman JE, Criswell DS (2007) Nitric oxide increases GLUT4 expression and regulates AMPK signaling in skeletal muscle. Am J Physiol Endocrinol Metab 293:E1062–E1068
Lira VA, Brown DL, Lira AK, Kavazis AN, Soltow QA, Zeanah EH, Criswell DS (2010) Nitric oxide and AMPK cooperatively regulate PGC-1 in skeletal muscle cells. J Physiol 15(588):3551–3566
Long YC, Zierath JR (2006) AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest 116(7):1776–1783
McConell GK, Ng GP, Phillips M, Ruan Z, Macaulay SL, Wadley GD (2010) Central role of nitric oxide synthase in AICAR and caffeine-induced mitochondrial biogenesis in L6 myocytes. J Appl Physiol 108:589–595
Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G, Lehman JJ, Kelly DP, Spiegelman BM (2001) Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci U S A 98:3820–3825
Miwa S, Brand MD (2003) Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling. Biochem Soc Trans 31:1300–1301
Mu J, Brozinick JT Jr, Valladares O, Bucan M, Birnbaum MJ (2001) A role for AMP activated protein kinase in contraction and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 7:1085–1094
Nemoto S, Fergusson MM, Finkel T (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1 α. Biol Chem 280:16456–16460
Nogueiras R, Habegger KM, Chaudhary N et al (2012) Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev 92(3):1479–1514
Patti ME et al (2003) Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A 100(14):8466–8471
Pattwell DM, McArdle A, Morgan JE, Patridge TA, Jackson MJ (2004) Release of reactive oxygen and nitrogen species from contracting skeletal muscle cells. Free Radic Biol Med 37:1064–1072
Pilegaard H, Saltin B, Neufer PD (2003) Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 546:851–858
Potthoff MJ, Wu H, Arnold MA, Shelton JM, Backs J, McAnally J, Richardson JA, Bassel-Duby R, Olson EN (2007) Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers. J Clin Investig 117:2459–2467
Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, Hubbard BP, Varela AT, Davis JG, Varamini B, Hafner A, Moaddel R, Rolo AP, Coppari R, Palmeira CM, de Cabo R, Baur JA, Sinclair DA (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15:675–690
Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829–839
Puigserver P, Spiegelman BM (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 24:78–90
Rhee SG, Chae HZ, Kim K (2005) Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med 38:1543–1552
St Clair DK, Porntadavity S, Xu Y, Kiningham K (2002) Transcription regulation of human manganese superoxide dismutase gene. Methods Enzymol 349:306–312
St-Pierre J, Lin J, Krauss S, Tarr PT, Yang R, Newgard CB, Spiegelman BM (2003) Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells. J Biol Chem 278:26597–26603
St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S et al (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408
Valle I, Alvarez-Barrientos A, Arza E, Lamas S, Monsalve M (2005) PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res 66:562–573
Wojtaszewski JF, Nielsen P, Hansen BF, Richter EA, Kiens B (2000) Isoform-specific and exercise intensity-dependent activation of 5′-AMP-activated protein kinase in human skeletal muscle. J Physiol 528:221–226
Wojtaszewski JF, Mourtzakis M, Hillig T, Saltin B, Pilegaard H (2002) Dissociation of AMPK activity and ACCbeta phosphorylation in human muscle during prolonged exercise. Biochem Biophys Res Commun 298:309–316
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Thirupathi, A., de Souza, C.T. Multi-regulatory network of ROS: the interconnection of ROS, PGC-1 alpha, and AMPK-SIRT1 during exercise. J Physiol Biochem 73, 487–494 (2017). https://doi.org/10.1007/s13105-017-0576-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13105-017-0576-y