Cytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise

Henríquez‐Olguín, Carlos; Knudsen, Jonas R.; Raun, Steffen H.; Li, Zhencheng; Dalbram, Emilie; Treebak, Jonas T.; Sylow, Lykke; Holmdahl, Rikard; Richter, Erik A.; Jaimovich, Enrique; Jensen, Thomas E.

doi:10.1101/522805

Cited by 31 publications

(48 citation statements)

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“…Rac1 is an essential component in the activation of the reactive oxygen-producing NADPH oxidase (NOX)-2 complex 26,27 . Recently, it was reported that NOX2 is required for exercise-stimulated glucose uptake 28 . Moreover, it was shown that exercise-induced NOX2 activation was completely abrogated in TA from muscle-specific Rac1 KO mice 28 , suggesting that Rac1 mainly regulates muscle glucose uptake through activation of NOX2 in response to exercise.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was reported that NOX2 is required for exercise-stimulated glucose uptake 28 . Moreover, it was shown that exercise-induced NOX2 activation was completely abrogated in TA from muscle-specific Rac1 KO mice 28 , suggesting that Rac1 mainly regulates muscle glucose uptake through activation of NOX2 in response to exercise. Alternatively, the Ral family GTPase, RalA could signal downstream of Rac1.…”

Section: Discussionmentioning

confidence: 99%

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The role of group I p21-activated kinases in contraction-stimulated skeletal muscle glucose transport

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Nielsen

et al. 2020

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20Aim: Muscle contraction stimulates skeletal muscle glucose transport. Since it occurs inde-21 pendently of insulin, it is an important alternative pathway to increase glucose uptake in insu-22 lin-resistant states, but the intracellular signalling mechanisms are not fully understood. Muscle 23 contraction activates group I p21-activated kinases (PAKs) in mouse and human skeletal mus-24 cle. PAK1 and PAK2 are downstream targets of Rac1, which is a key regulator of contraction-25 stimulated glucose transport. Thus, PAK1 and PAK2 could be downstream effectors of Rac1 26 in contraction-stimulated glucose transport. The current study aimed to test the hypothesis that 27 PAK1 and/or PAK2 regulate contraction-induced glucose transport. Methods: Glucose 28 transport was measured in isolated soleus and extensor digitorum longus (EDL) mouse skeletal 29 muscle incubated either in the presence or absence of a pharmacological inhibitor (IPA-3) of 30 group I PAKs or originating from whole-body PAK1 knockout (KO), muscle-specific PAK2 31 (m)KO or double whole-body PAK1 and muscle-specific PAK2 knockout mice. Results: IPA-32 3 attenuated (-22%) the increase in muscle glucose transport in response to electrically-stimu-33 lated contraction. PAK1 was dispensable for contraction-stimulated glucose uptake in both so-34 leus and EDL muscle. Lack of PAK2, either alone (-13%) or in combination with PAK1 (-35 14%), reduced contraction-stimulated glucose transport compared to control littermates in 36 EDL, but not soleus muscle. Conclusion: Contraction-stimulated glucose transport in isolated 37 glycolytic mouse EDL muscle is partly dependent on PAK2, but not PAK1. 38 Keywords 39 Contraction; Glucose uptake, Metabolism; p21-activated kinase; Skeletal muscle.40 41Muscle contraction increases skeletal muscle glucose uptake independently of insulin 1-3 . Ac-42 cordingly, muscle contraction increases glucose uptake in both insulin-sensitive and insulin-43 resistant skeletal muscle 4-6 . Additionally, insulin sensitivity is improved after cessation of 44 muscle contraction 7-10 , making muscle contraction during acute exercise a non-pharmacolog-45 ical treatment for insulin resistance 11 . However, while muscle contraction is known to promote 46 the translocation of the glucose transporter (GLUT)-4 to the plasma membrane, which facili-47 tates glucose entry into the muscle, the intracellular signalling regulating this process is not 48 completely understood. 49Upon muscle contraction, multiple intracellular signalling pathways are activated that promote 50 GLUT4 translocation and a subsequent increase in muscle glucose transport. Redundant Ca +2 -51 dependent signalling, metabolic stress signalling, and mechanical stress signalling are proposed 52 to regulate distinct steps important for glucose transport in response to muscle contraction 12 . 53The group I p21-activated kinase (PAK)-1 and PAK2 are activated in response to electrical 54 pulse stimulation in C2C12 myotubes 13,14 and muscle contraction/acute exercise in mouse and 55 human sk...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The role of group I p21-activated kinases in contraction-stimulated skeletal muscle glucose transport

Llv

Nielsen

et al. 2020

Preprint

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“…Overproduction of ROS induced by unaccustomed, exhaustive exercise training or other stresses can lead to oxidative stress-related tissue damage and reduced contractility [85,86]. NADPH oxidases are major contributors to ROS production [87,88]. Previous work showed that physical stretching can increase the activity of NADPH oxidase, especially NOX2, to produce ROS in microtubule-dependent process [89].…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle DNMT3A plays a necessary role in endurance exercise by regulating oxidative capacity of red muscles

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Exercise interventions alter the DNA methylation profile in skeletal muscle, yet little is known about the role of the DNA methylation machinery in exercise capacity. In this study, we found that in oxidative red muscle, DNMT3A expression increases greatly following a bout of endurance exercise. Mice lacking Dnmt3a in skeletal muscle fibers had reduced tolerance to endurance exercise, accompanied by reduced oxidative capacity and reduced mitochondrial counts. Moreover, during exercise, the knockout muscles overproduced reactive oxygen species (ROS), which are major contributors to muscle dysfunction. In mechanistic terms, we demonstrated that Aldh1l1 is a key target of repression by DNMT3A in red muscles.DNMT3A directly regulated the Aldh1l1 transcription by binding to the Aldh1l1 promoter region and altering DNA methylation and histone modification. Enforcing ALDH1L1 expression, leading to elevated NADPH, led to overproduction of ROS by the NADPH oxidase complex (NOX) in myotubes, ultimately resulting in mitochondrial defects. Moreover, both genetic inhibition of ALDH1L1 and pharmacological inhibition of NOX rescued oxidative stress and mitochondrial decline in Dnmt3a-deficient myotubes, confirming the essential role of ALDH1L1-dependent ROS generation as a downstream effector of DNMT3A loss of function. Together, our results reveal that DNMT3A in skeletal muscle plays a pivotal role in endurance exercise by controlling intracellular oxidative stress. 10].Reactive oxygen species (ROS), including oxygen-derived molecules such as hydrogen peroxide (H2O2) and free radicals such as superoxide (•O2 −) and hydroxyl radical (HO•), cause oxidative stress [11,12] . A moderate increase in skeletal muscle ROS production in the acute phase of exercise is thought to activate signaling pathways that lead to cellular adaptation, thereby protecting against future stress [13][14][15][16][17].However, excessive ROS can oxidatively damage macromolecules including DNA, lipids, and proteins, as well as modify cellular redox status and cellular functions; consequently, ROS elevation is also associated with pathophysiological states of muscle and contractile dysfunction [13][14][15][16]. Mitochondria make a large contribution to ROS production at rest, but not during muscle contraction [13,[17][18][19]. The majority of ROS produced during contraction arise from non-mitochondrial sources, such as NADPH oxidase (NOX), located in the microtubules [16,20,21] . The redox-mediated crosstalk between NOX and mitochondria exacerbates ROS production and disrupts redox homeostasis [21][22][23][24]. For example, NOX-derived ROS promote the opening of mitochondrial ATP-sensitive K+ channels [23][24][25]. The resultant potassium influx into the matrix lowers the mitochondrial membrane potential, which causes mitochondrial swelling, opening of permeability transition pores, and elevated ROS production [23][24][25]. In addition, NOX-derived ROS causes leakage of Ca2+ from the sarcoplasmic reticulum or entry of extracellular Ca2+, resulting in mitocho...

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“…The literature quantified in the following refers to both animals and humans (mice, 18 studies [68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85]; rats, 6 studies [86][87][88][89][90][91]; and humans, 3 studies [73,92,93]; one study used both mice and humans [73]. There was no restriction to the type of acute exercise used.…”

Section: The Quantitative Effect Of Exercise On Rons Levels In Musclementioning

confidence: 99%

“…Most animal studies used electrical stimulation (either on muscle cells or on whole muscle [68-72, 75, 76, 78-85, 87-91] and only 4 animal studies used a more physiological type of exercise (i.e., endurance exercise on a treadmill [73,74,77,86]. The 3 human studies used different exercise protocols (endurance exercise on a bicycle or treadmill and resistance exercise [73,92,93]. Relevant studies that employed non-physiological exercise models, namely in vitro muscle stimulation or in situ muscle stimulation, are also included.…”

Section: The Quantitative Effect Of Exercise On Rons Levels In Musclementioning

confidence: 99%

Quantitative Redox Biology of Exercise

2020

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Biology is rich in claims that reactive oxygen and nitrogen species are involved in every biological process and disease. However, many quantitative aspects of redox biology remain elusive. The important quantitative parameters you need to address the feasibility of redox reactions in vivo are: rate of formation and consumption of a reactive oxygen and nitrogen species, half-life, diffusibility and membrane permeability. In the first part, we explain the basic chemical kinetics concepts and algebraic equations required to perform “street fighting” quantitative analysis. In the second part, we provide key numbers to help thinking about sizes, concentrations, rates and other important quantities that describe the major oxidants (superoxide, hydrogen peroxide, nitric oxide) and antioxidants (vitamin C, vitamin E, glutathione). In the third part, we present the quantitative effect of exercise on superoxide, hydrogen peroxide and nitric oxide concentration in mitochondria and whole muscle and calculate how much hydrogen peroxide concentration needs to increase to transduce signalling. By taking into consideration the quantitative aspects of redox biology we can: i) refine the broad understanding of this research area, ii) design better future studies and facilitate comparisons among studies, and iii) define more efficiently the “borders” between cellular signaling and stress.

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Cytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise

Cited by 31 publications

References 40 publications

The role of group I p21-activated kinases in contraction-stimulated skeletal muscle glucose transport

The role of group I p21-activated kinases in contraction-stimulated skeletal muscle glucose transport

Skeletal muscle DNMT3A plays a necessary role in endurance exercise by regulating oxidative capacity of red muscles

Quantitative Redox Biology of Exercise

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