Abstract
The contractile function of striated muscle cells is altered by oxidative/nitrosative stress, which can be observed under physiological conditions but also in diseases like heart failure or muscular dystrophy. Oxidative stress causes oxidative modifications of myofilament proteins and can impair myocyte contractility. Recent evidence also suggests an important effect of oxidative stress on muscle elasticity and passive stiffness via modifications of the giant protein titin. In this review we provide a short overview of known oxidative modifications in thin and thick filament proteins and then discuss in more detail those oxidative stress-related modifications altering titin stiffness directly or indirectly. Direct modifications of titin include reversible disulfide bonding within the cardiac-specific N2-Bus domain, which increases titin stiffness, and reversible S-glutathionylation of cryptic cysteines in immunoglobulin-like domains, which only takes place after the domains have unfolded and which reduces titin stiffness in cardiac and skeletal muscle. Indirect effects of oxidative stress on titin can occur via reversible modifications of protein kinase signalling pathways (especially the NO-cGMP-PKG axis), which alter the phosphorylation level of certain disordered titin domains and thereby modulate titin stiffness. Oxidative stress also activates proteases such as matrix-metalloproteinase-2 and (indirectly via increasing the intracellular calcium level) calpain-1, both of which cleave titin to irreversibly reduce titin-based stiffness. Although some of these mechanisms require confirmation in the in vivo setting, there is evidence that oxidative stress-related modifications of titin are relevant in the context of biomarker design and represent potential targets for therapeutic intervention in some forms of muscle and heart disease.
Highlights
Oxidative stress as an important modifier of myocyte propertiesOxidative stress occurs in the cell when reactive oxygen/ nitrogen species (ROS/RNS) are increased or when the antioxidant defence mechanisms are decreased; i.e., when one or both of these factors go out of balance
In this review we provide a short overview of known oxidative modifications in thin and thick filament proteins and discuss in more detail those oxidative stress-related modifications altering titin stiffness directly or indirectly
Indirect effects of oxidative stress on titin can occur via reversible modifications of protein kinase signalling pathways, which alter the phosphorylation level of certain disordered titin domains and thereby modulate titin stiffness
Summary
Oxidative stress occurs in the cell when reactive oxygen/ nitrogen species (ROS/RNS) are increased or when the antioxidant defence mechanisms are decreased; i.e., when one or both of these factors go out of balance. Among the targets of oxidative modification are various contractile and regulatory proteins of the sarcomeres, the structural and functional units of striated muscle. Oxidative modification of these myofilament proteins can have dramatic functional consequences, including altered calcium sensitivity of force production, contractile impairment and muscle. ROS/RNS can alter miscellaneous cellular properties by reacting with amino acids in proteins. These proteins are modified either reversibly (i.e., the oxidized protein can be enzymatically repaired) or irreversibly (i.e., the oxidized protein must be replaced by de novo synthesis), depending on the nature and amount of ROS (Canton et al 2014). We make a case for the emerging importance of oxidative modifications of the titin springs in regulating myocyte elasticity and ‘passive’ stiffness under oxidative stress conditions
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