The "Goldilocks Zone" from a redox perspective-Adaptive vs. deleterious responses to oxidative stress in striated muscle

Abstract

Consequences of oxidative stress may be beneficial or detrimental in physiological systems. An organ system's position on the "hormetic curve" is governed by the source and temporality of reactive oxygen species (ROS) production, proximity of ROS to moieties most susceptible to damage, and the capacity of the endogenous cellular ROS scavenging mechanisms. Most importantly, the resilience of the tissue (the capacity to recover from damage) is a decisive factor, and this is reflected in the disparate response to ROS in cardiac and skeletal muscle. In myocytes, a high oxidative capacity invariably results in a significant ROS burden which in homeostasis, is rapidly neutralized by the robust antioxidant network. The up-regulation of key pathways in the antioxidant network is a central component of the hormetic response to ROS. Despite such adaptations, persistent oxidative stress over an extended time-frame (e.g., months to years) inevitably leads to cumulative damages, maladaptation and ultimately the pathogenesis of chronic diseases. Indeed, persistent oxidative stress in heart and skeletal muscle has been repeatedly demonstrated to have causal roles in the etiology of heart disease and insulin resistance, respectively. Deciphering the mechanisms that underlie the divergence between adaptive and maladaptive responses to oxidative stress remains an active area of research for basic scientists and clinicians alike, as this would undoubtedly lead to novel therapeutic approaches. Here, we provide an overview of major types of ROS in striated muscle and the divergent adaptations that occur in response to them. Emphasis is placed on highlighting newly uncovered areas of research on this topic, with particular focus on the mitochondria, and the diverging roles that ROS play in muscle health (e.g., exercise or preconditioning) and disease (e.g., cardiomyopathy, ischemia, metabolic syndrome).

Keywords: adaptation; carbonyl stress; heart; hormesis; lipid peroxidation; mitochondria; redox environment; skeletal muscle.

Figure 1

Oxidative stress adaptations in striated muscle and the Goldilocks Zone. The concept of the Goldilocks Zone in the redox environment of striated muscle is illustrated in the schematics shown above. Time-dependent changes in tissue oxidative stress due to exercise (green line) is pulsatile in nature, coming from consecutive bouts of exercise over time, whereas the oxidative stress arising from cardio-metabolic diseases (red line) is persistent. As depicted in (A), the ultimate outcome of these two stressors is divergent, since exercise-induced ROS over time keeps the myocytes well within the Goldilocks Zone of homeostasis (region between the Reducing and Oxidative stress, two dashed black lines), while disease-induced ROS eventually pushes the myocytes outside of the Zone, leading to deleterious consequences (e.g., unresolved inflammation, electro-mechanical dysfunction, mitochondrial dysfunction and cell death). These divergent outcomes are best explained by the adaptive responses in the antioxidant capacity and cell quality control mechanisms that are elicited by these two sources of oxidative stress. (B) Illustrates this adaptive response, in that exercise-induced ROS leads to augmentation of the antioxidant capacity and protection against exogenous stressors over time. Conversely, disease-induced ROS, due to its persistent and insidious nature, ultimately overwhelms endogenous protective mechanisms, ultimately resulting in a maladaptive response.

Figure 2

Cell signaling pathways underlying ROS adaptation in striated muscle. The beneficial and deleterious consequences of oxidative stress coming from cardio-metabolic diseases (top) or exercise (bottom) in striated muscle at the subcellular level are shown here. Note the difference in designation of solid-line arrows for the persistent ROS coming from disease, compared to dashed-line arrows representing the pulsatile ROS coming from exercise. Formation of lipid peroxides and their derivative aldehydes such as 4-hydroxynonenal (HNE), along with their subsequent reactivity to cause protein carbonylation and carbonyl stress is depicted by yellow lightning bolts in cytosol and mitochondria. (NOX, NADPH oxidase; HFHS, high fat, high sucrose; PUFA, polyunsaturated fatty acids; FFA, free fatty acids; AA, arachidonic acid; PLA₂, phospholipase A₂; PPAR, peroxisome proliferator-activated receptor; ANT, adenine nucleotide translocase; COX IV, cytochrome oxidase IV; ATP, adenosine tri-phosphate; Nrf2, NF E2-related factor 2; NRF1, nuclear respiratory factor 1; GST, glutathione S-transferase; ALDH2, aldehyde dehydrogenase 2; GCLC, γ-Glutamylcysteine ligase catalytic subunit; GPx, glutathione peroxidase; NQO-1, NADPH-quinone oxido-reductase-1; GR, glutathione reductase; GSHt, total glutathione; Trx, thioredoxin; TxnRd2, thioredoxin reductase-2; MAO, monoamine oxidase; MnSOD, manganese superoxide dismutase; CAT, catalase).

Figure 3

Pre-conditioning and ROS-mediated effects in striated muscle. Shown is a schematic illustrating the development of ROS-mediated adaptations from various preconditioning paradigms as described in the text. Adaptive responses that lead to preconditioning in cardiac muscle culminate in protection through early post-translational modifications to redox sensitive enzymes, and late adaptations through enhanced translocation of key transcription factors. The ensuing adaptations result in the early- and late-window of preconditioning that have been described in the cardioprotection literature. (ROS, Reactive oxygen species; NOX, NADPH-oxidase; ETS, Electron transport system; MAO, Monoamine oxidase; Nrf2, NF E2-related factor-2; HIF1α, Hypoxia-inducible factor-1α; Autocoids, factors secreted from cells with paracrine-like effects).