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).

Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase

“…It is quite possible that exercise training induces an upregulation in the H 2 O 2 detoxification pathways in the obese, such as the glutathione and thioredoxin systems, catalase, and the Nrf2/Keap1 phase II antioxidant system. 38 As H 2 O 2 has a longer half-life and is much more membrane permeable than superoxide, it is very plausible that some of the H 2 O 2 detected via microdialysis is mitochondria derived. In this context, it is also likely that exercise training in the obese subjects promotes a reduction in mitochondrial derived ROS emission, which could manifest as reduced interstitial H 2 O 2 .…”

Redox regulation of autophagy in skeletal muscle

“…In contrast, high levels of ROS result in damage to cellular components such as proteins and organelles, leading to muscle dysfunction. The role of ROS and oxidative stress in the regulation of skeletal muscle has been extensively reviewed elsewhere (74–81) as well as in this Special Issue.…”

“…There are a number of potential sources of ROS production in skeletal muscle. These include mitochondria, NADPH oxidase (Nox), xanthine oxidase, and phospholipase A2 (reviewed in (74, 75)). However, mitochondria and Nox isoform 2 (Nox2) have emerged as the two main sources of ROS production.…”

Exercise-induced protection against reperfusion arrhythmia involves stabilization of mitochondrial energetics

“…Improved endogenous scavenging in the heart following exercise is clear (5,27). It is plausible that Ex mitochondria also produce less ROS.…”