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Nox4 Mediates Skeletal Muscle Metabolic Responses to Exercise University of Massachusetts Medical School eScholarship@UMMS Open Access Publications by UMMS Authors 2021-03-01 Nox4 mediates skeletal muscle metabolic responses to exercise Kalyn S. Specht Virginia Polytechnic Institute and State University Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Biochemical Phenomena, Metabolism, and Nutrition Commons, Exercise Physiology Commons, Exercise Science Commons, and the Musculoskeletal System Commons Repository Citation Specht KS, Kant S, Learnard H, Campbell M, Caliz AD, Pei Y, Reif MM, Keaney JF, Craige SM. (2021). Nox4 mediates skeletal muscle metabolic responses to exercise. Open Access Publications by UMMS Authors. https://doi.org/10.1016/j.molmet.2020.101160. Retrieved from https://escholarship.umassmed.edu/ oapubs/4557 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Publications by UMMS Authors by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Brief Communication Nox4 mediates skeletal muscle metabolic responses to exercise Kalyn S. Specht 1, Shashi Kant 2,3, Adele K. Addington 1, Ryan P. McMillan 1,4, Matthew W. Hulver 1, Heather Learnard 2, Maura Campbell 2, Sarah R. Donnelly 1, Amada D. Caliz 2,3, Yongmei Pei 2, Michaella M. Reif 2, Jacob M. Bond 1,5, Anthony DeMarco 1, Branch Craige 6, John F. Keaney Jr. 2,3, Siobhan M. Craige 1,2,* ABSTRACT Objective: The immediate signals that couple exercise to metabolic adaptations are incompletely understood. Nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) produces reactive oxygen species (ROS) and plays a significant role in metabolic and vascular adaptation during stress conditions. Our objective was to determine the role of Nox4 in exercise-induced skeletal muscle metabolism. Methods: Mice were subjected to acute exercise to assess their immediate responses. mRNA and protein expression responses to Nox4 and hydrogen peroxide (H2O2) were measured by qPCR and immunoblotting. Functional metabolic flux was measured via ex vivo fatty acid and glucose oxidation assays using 14C-labeled palmitate and glucose, respectively. A chronic exercise regimen was also utilized and the time to exhaustion along with key markers of exercise adaptation (skeletal muscle citrate synthase and beta-hydroxyacyl-coA-dehydrogenase activity) were measured. Endothelial-specific Nox4-deficient mice were then subjected to the same acute exercise regimen and their subsequent substrate oxidation was measured. Results: We identified key exercise-responsive metabolic genes that depend on H2O2 and Nox4 using catalase and Nox4-deficient mice. Nox4 was required for the expression of uncoupling protein 3 (Ucp3), hexokinase 2 (Hk2), and pyruvate dehydrogenase kinase 4 (Pdk4), but not the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1a). Global Nox4 deletion resulted in decreased UCP3 protein expression and impaired glucose and fatty acid oxidization in response to acute exercise. Furthermore, Nox4-deficient mice demonstrated impaired adaptation to chronic exercise as measured by the time to exhaustion and activity of skeletal muscle citrate synthase and beta- hydroxyacyl-coA-dehydrogenase. Importantly, mice deficient in endothelial-Nox4 similarly demonstrated attenuated glucose and fatty acid oxidation following acute exercise. Conclusions: We report that H2O2 and Nox4 promote immediate responses to exercise in skeletal muscle. Glucose and fatty acid oxidation were blunted in the Nox4-deficient mice post-exercise, potentially through regulation of UCP3 expression. Our data demonstrate that endothelial-Nox4 is required for glucose and fatty acid oxidation, suggesting inter-tissue cross-talk between the endothelium and skeletal muscle in response to exercise. Ó 2021 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords Exercise; Nox4; ROS; Metabolic adaptation; Skeletal muscle metabolism; Endothelium 1. INTRODUCTION angiogenesis and mitochondrial biogenesis and enhances glucose and lipid metabolism [1]. These changes in skeletal muscle metabolism are Skeletal muscle is an extraordinarily plastic tissue that quickly re- critically linked to skeletal muscle health and systemic metabolism. sponds to repeated contractions in an effort to supply sufficient Therefore, understanding the initiating stimuli that trigger exercise- adenosine triphosphate (ATP) for working muscle. Exercise is a potent mediated metabolic adaptation is important to characterize the un- strategy to reduce muscle wasting and prevent many chronic vascular derlying molecular signaling involved in the health benefits of exercise. and metabolic diseases. A single bout of exercise elicits the immediate Skeletal muscle produces reactive oxygen species (ROS) during ex- upregulation of mRNA expression associated with metabolic adapta- ercise [2]. ROS levels are also increased in subjects with muscular tion, stimulation of glucose and fatty acid transport, and increased diseases, leading to fatigue and atrophy [3]. Therefore, ROS production substrate oxidation (glucose and fatty acid) [1]. Consistent, repeated during exercise was initially thought to be solely deleterious. However, bouts of exercise over weeks to months (chronic exercise) increases multiple studies have demonstrated that, in healthy adults, ROS- 1Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA, 24061, USA 2Division of Cardiovascular Medicine, Department of Medicine, University of Massa- chusetts Medical School, Worcester, MA, 01655, USA 3Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA 4Metabolism Core, Virginia Tech, Blacksburg, VA, 24061, USA 5Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Roanoke, VA, 24016, USA 6Department of Biochemistry, Virginia Tech, Blacksburg, VA, 24061, USA *Corresponding author. Human Nutrition, Foods, and Exercise, Virginia Tech, 1012, ILSB, 1981 Kraft Drive, Virginia Tech Corporate Research Center, Blacksburg, VA, 24061, USA. E-mail: [email protected] (S.M. Craige). Received November 7, 2020 Revision received December 15, 2020 Accepted December 30, 2020 Available online 2 January 2021 https://doi.org/10.1016/j.molmet.2020.101160 MOLECULAR METABOLISM 45 (2021) 101160 Ó 2021 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1 www.molecularmetabolism.com Brief Communication responsive signaling pathways are important for improved glucose acclimated to the treadmill for 3 days prior to the exercise regimens. On metabolism and increased efficiency of mitochondrial function in day 1, the mice were allowed to stand on the stationary treadmill for response to exercise [4]. Specifically, human studies have demon- 15 min. On day 2, the mice walked on the treadmill at 5 m/min for strated that quenching the ROS signal with antioxidant supplementa- 15 min. On day 3, the mice began walking at 5 m/min; the treadmill tion attenuates increased insulin sensitivity and mitochondrial speed was gradually increased to 15 m/min and the mice ran at this biogenesis [5]. While studies have documented that exercise-induced speed for 15 min. To control for any non-exercise effects of treadmill ROS promote muscle adaptation to exercise, the source(s) and target(s) running (handling, novel environment, noise, and vibrations), the non- of these ROS are largely unknown. exercised group of mice (SED) was placed on the top of the treadmill Several lines of evidence suggest that exercise promotes ROS produc- apparatus for an identical period of time. The mice were not subjected to tion in the skeletal muscle from multiple sources (Nox2, Nox4, mito- electric shock during the treadmill sessions to avoid stress. chondria, and xanthine oxidase) [6e11]. However, NADPH oxidase (Nox) The chronic exercise training consisted of treadmill running for 60 min/ enzymes contribute to cytosolic ROS production both at rest and during day at 18 m/min 5 days/week for 4 weeks. Tissue was harvested contraction [6]. The Nox family of enzymes transfers electrons from >24 h following the last exercise bout. NADPH to molecular oxygen, producing ROS. Inhibition of Nox enzymes The exhaustive exercise protocol [18] began at 5 m/min for 15 min blocks both basal and stretch/contraction-stimulated skeletal muscle followed by gradual increases in speed at 3 min intervals until the ROS production [6,10]. Skeletal muscle is a mixed tissue; its paren- treadmill speed reached 24.25 m/min, at which point it was held at this chyma consists of myofibers while its stromal composition includes speed for 30 min or until the mice reached exhaustion. The state of myocytes, endothelial cells, pericytes, and immune cells. Thus, Nox’s exhaustion was established by a mouse remaining in the lower quarter contribution to skeletal muscle ROS production is likely significantly of the treadmill 3 cumulative times despite gentle encouragement. influenced by its expression patterns in these different cell types. The acute exercise protocol consisted of a 60 min
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