Mechanisms of Oxidative Damage and Their Impact on Contracting Muscle

Abstract

An atom or a group of atoms that contains one or more unpaired electron(s) is termed a free radical, which is often a highly reactive and unstable molecule. Two groups of these radical molecules are often classified as reactive oxygen and reactive nitrogen species, respectively. Stabilisation of these radicals requires electron donation from proteins, lipids and DNA which oftentimes leads to degradation and damage to these molecules. Owing to the potential for cellular damage, much controversy was created by initial reports that indicated that physical exercise increased the production of reactive oxygen species (ROS) (Dillard et al. 1978). This initial work did not reveal the specific location, but later work revealed the contracting skeletal muscle to be a prominent source of ROS (Davies et al. 1982). Years later, it was also revealed that contracting muscles also produced nitric oxide (NO), the predominant parent molecule of reactive nitrogen species (Balon and Nadler 1994), and a number of well-constructed review articles since then have confirmed the contribution of skeletal muscle to the production of both ROS and reactive nitrogen species (Powers and Jackson 2008, Jackson 2009, Powers et al. 2011).The most abundant biological free radicals are formed when oxygen or nitrogen is incompletely reduced, leading to the production of superoxide ( ) and NO, processes which will be explained in greater detail later in the chapter. The superoxide parent molecule can subsequently be converted into other ‘radicals’, namely hydrogen peroxide (H2O2) and the hydroxyl radical (•OH). Removal of ROS is managed by a host of antioxidant systems (e.g. catalase, glutathione/thiol regulation) in the body, and the balance of oxygen species to antioxidants is termed the ‘redox state’. As mentioned previously, dysregulation of the redox state results in radical scavenging of key biomolecules such as proteins, lipids (cell membranes are a common target) and DNA, a process which can leave them damaged and unable to function. For these reasons, early theories in the 1980s and 1990s led to the belief that ROS production was mostly a negative consequence of physical exercise. Furthermore, evidence began to mount that a number of clinical situations such as heart disease, amyotrophic lateral sclerosis, irritable bowel disease, diabetes and ageing were a consequence of excessive ROS production and free radical damage (Sies 1985, Powers and Jackson 2008, Jackson 2009, Tsutsui et al. 2011).Recent perspectives, however, have begun to highlight the fact that both oxygen and nitrogen species exert a key role in the regulation of many intracellular mechanisms and also contribute significantly to various cellular signalling pathways involved with muscle adaptation. For example, several studies and review articles have highlighted the fact that controlled production of both reactive species contribute to mitochondrial biogenesis, angiogenesis, skeletal muscle hypertrophy and proper immune function (Ji et al. 2006, Jackson 2009, Powers et al. 2010, 2011). In this respect, it appears that maintaining a proper balance between radical production and removal is a vital physiological process in the body. The purpose of this chapter is first to briefly explain the main pathways in the human body, which lead to free radical production, and then to highlight the impact of free radical regulation in both cardiac and skeletal muscle tissues. It is these pathways upon which many of the proposed theories for antioxidant regulation occur through manipulation of training, environment, diet or supplementation of the diet with ingredients purported to favourably alter the cellular antioxidant milieu.