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Effects of S-glutathionylation, S-nitrosylation and oxidation on Ca-sensitivity and force: a balancing act

G.D. Lamb, J.P. Mollica, T.L. Dutka, G.S. Posterino and R.M. Murphy, Department of Zoology, La Trobe University, Melbourne, VIC 3086, Australia.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important for skeletal muscle function both in physiological and pathological conditions. These agents are generated in active muscle and can induce both acute and long term effects on muscle function. Exposure of intact fast-twitch muscle fibres to the oxidant hydrogen peroxide (H2O2) affects force principally by altering myofibrillar Ca2+ sensitivity, initially producing increased sensitivity, followed by a decrease with more prolonged exposure (Andrade et al., 1998). Experiments on skinned fibres show that these effects can be attributed to H2O2 interacting with glutathione and myoglobin, causing S-glutathionylation and oxidation of the contractile apparatus respectively (Lamb & Posterino, 2003; Murphy et al., 2008). H2O2 can also oxidize the sarcoplasmic reticulum Ca2+ release channels, the ryanodine receptors, and studies on isolated channels show that this oxidation has a large stimulatory effect on Ca2+-induced Ca2+ release. However, experiments on skinned and intact fibres show that acute H2O2-induced oxidation has little or no effect on action potential-induced Ca2+ release, the normal physiological process governing Ca2+ release (Posterino et al., 2003). Application of nitric oxide donors, on the other hand, produce a decrease in submaximal force in skinned muscle fibres, due primarily to a decrease in myofibrillar Ca2+ sensitivity (Spencer & Posterino, 2009), brought about by S-nitrosylation of the contractile apparatus. More extensive exposure of muscle to oxidants or nitrosylating agents can also lead to a decrease in both maximum force and Ca2+-sensitivity of the contractile apparatus, likely due primarily to oxidation of reactive sulphydryls in the myosin heads. The overall effect on muscle function of ROS and RNS generated in physiological and pathological conditions is determined by the balance of these conflicting actions of S-glutathionylation, S-nitrosylation and oxidation.

Andrade FH, Reid MB, Allen DG & Westerblad H. (1998) Journal of Physiology 509, 565-575.

Lamb GD & Posterino GS. (2003) Journal of Physiology 546, 149-163.

Murphy RM, Dutka TL & Lamb GD. (2008) Journal of Physiology 586, 2203-2216.

Posterino GS, Cellini MA & Lamb GD. (2003) Journal of Physiology 547, 807-823.

Spencer T & Posterino GS. (2009) American Journal of Physiology. Cell Physiology 296, C1015-1023.