Compartmentalized muscle redox signals controlling exercise metabolism - Current state, future challenges

Abstract

Exercise imposes cellular stress on contracting skeletal muscle fibers, forcing them to complete molecular adaptations to maintain homeostasis. There is mounting evidence that redox signaling by reactive oxygen species (ROS) is vital for skeletal muscle exercise adaptations across many different exercise modalities. The study of redox signaling is moving towards a growing appreciation that these ROS do not signal in a global unspecific way, but rather elicit their effects in distinct subcellular compartments. This short review will first outline the sources of ROS in exercising skeletal muscle and then discuss some examples of exercise adaptations, which are evidenced to be regulated by compartmentalized redox signaling. We speculate that knowledge of these redox pathways might one day allow targeted manipulation to increase redox-signaling in specific compartments to augment the exercise-hormetic response in health and disease.

Keywords: Exercise; Metabolism; Mitochondria; NADPH oxidase; Reactive oxygen species; Skeletal muscle.

Fig. 1

Overview of major oxidant and antioxidant systems contributing to compartmentalized reactive oxygen species (ROS) generation during skeletal muscle contraction. A) In the cytosol (top left), current evidence suggests that cytosolic H₂O₂ generated by NAPDH oxidase (NOX) 2 is a major regulator of exercise-stimulated ROS. NOX4, reported on the sarcoplasmic reticulum (SR) and mitochondrial intermembrane space (IMS in top left panel) has also been linked to several physiological endpoints in skeletal muscle. H₂O₂ generated by both sources are removed by an intricate antioxidant defense network which may itself be compartmentalized. In mitochondria, sources of ROS include the electron transport chain (ETC) and NOX4. Mitochondrial ROS may signal locally within their compartment of origin or traverse the mitochondrial membranes, likely as H₂O₂ assisted by various channels. Mitochondrial ROS is removed by mitochondria-specific antioxidant proteins. B) Cytosolic ROS increases during acute exercise-bouts and has been linked to multiple physiological adaptations. Mitochondrial ROS do not seem to increase during acute exercise-bouts, but have been suggested to increase post-exercise, where they may regulate processes such as mitophagy. IMS, intermembrane space; ETC, electron transport chain; AQP, aquaporin; VDAC, voltage-dependent anion channel; O₂^•−, superoxide anion; H₂O₂, hydrogen peroxide; NOX2, nicotinamide adenine dinucleotide phosphate oxidase 2; NOX4, nicotinamide adenine dinucleotide phosphate oxidase 4; SOD1, superoxide dismutase 1; SOD2, superoxide dismutase 2; SOD3, superoxide dismutase 3; TrxR1, thioredoxin reductase; TrxR2, thioredoxin reductase 2; Trx1, thioredoxin 1; Trx2, thioredoxin 2; Prx1, peroxiredoxin 1; Prx2, peroxiredoxin 2; Prx3, peroxiredoxin 3; CAT, catalase; GSH, reduced glutathione; GSSG, glutathione disulfide; GPx1, glutathione peroxidase 1; GPx4, glutathione peroxidase 4; GSHR, glutathione disulfide reductase. Oxidized proteins are shown in red. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Examples of exercise-regulated endpoints linked to compartmentalized redox-signaling. Across the exercise-continuum, cytosolic redox-signaling has been described to regulate different processes. During endurance-type exercise, NOX2 activity-likely residing within or near the surface-membrane - is required for exercise-stimulated GLUT4 translocation to stimulate glucose uptake. We speculate in this review that this may involve TXNIP or CaMKII, two redox-sensitive proteins previously linked to GLUT4 translocation. NOX2 activity may also regulate translocation of transcription factors such as NF-κB to regulate antioxidant defense. This may involve redox-sensitive proteins such as p38 MAPK and IKKy. Prx2 may act as a cytosolic intermediate in redox signal transduction. In response to mechanical stress during resistance-type exercise, NOX4 and nNOS have, via their convergence product peroxinitrite (ONOO^-), been proposed to regulate Trpv1-dependent Ca²⁺ release to activate mTORC1 and stimulate muscle hypertrophy. Mitochondria are unlikely to increase their net ROS levels during exercise but increased mitochondrial ROS post-exercise may signal to regulate e.g. mitophagy. NOX2, NADPH oxidase 2; NOX4, NADPH oxidase 4; SR, sarcoplasmic reticulum; nNOS (β), neuronal nitric oxide synthase β; nNOS (μ), neuronal nitric oxide synthase μ; O₂^•−, superoxide anion; H₂O₂, hydrogen peroxide; Prx2, peroxiredoxin 2; Trx1, thioredoxin 1; TXNIP; thioredoxin (Trx)-interacting protein; CaMKII, calcium/calmodulin-dependent protein kinase type II; p38 mitogen-activated protein (MAP) kinases; IKKγ, IκB kinase γ; NF-κB, Nuclear factor-κB; SOD2, superoxide dismutase 2; GPx, glutathione peroxidase; NO, nitric oxide; ONOO-, peroxynitrite; Trpv1, transient receptor potential vanilloid 1; Ca²⁺, calcium; mTORC1, mechanistic target of rapamycin complex 1.