Reducing Inflammation and Oxidative Stress in Muscular Dystrophy

Because primary defects in muscular dystrophies often contribute to increased incidence of myofiber/myofibril damage and degeneration, elevated activity of the acute inflammatory response is a prevalent attribute of dystrophic muscles. It is well established that a functioning inflammatory cell population is essential for timely elimination of the damaged and degenerating muscle fibers prior to initiation of myofiber/myofibril regeneration. However, it is also clear that overactive inflammatory cell responses may adversely affect muscle structure and function in severe dystrophies (Nguyen and Tidball 2003a; Tidball and Wehling-Henricks 2005; Dudley et al. 2006). In particular, the local generation and release of reactive oxygen species as a consequence of inflammatory cell activation within dystrophic muscles imposes increased oxidative stress upon myofibers, which in conjunction with metabolic stress as a consequence of compromised microvascular circulation can increase the potential for further myofiber/myofibril damage (Tidball and Wehling-Henricks 2007).

In regard to reducing inflammation and oxidative stress in dystrophic muscles, the role of nitric oxide synthase (NOS) and its production of nitric oxide (NO) have received considerable attention. In DMD, the loss of dystrophin is associated with reduced levels of neuronal NOS in muscle (Brenman et al. 1995; Kasai et al. 2004), which in turn is thought to potentially contribute to increased oxidative stress (Brenman et al. 1995). Furthermore, because NO acts as a vasodilator, its loss in muscular dystrophy can render vessels less responsive to vasodilatory mechanisms leading at least to reduced exercise performance, and at worst, damage-inducing ischemia (Thomas et al. 1998; Sander et al. 2000; Dudley et al. 2006; Kobayashi et al. 2008). Importantly, the reduction of NO levels appears to reduce the anti inflammatory signals within dystrophic muscles, which may cause undesirable escalation of acute inflammatory processes subsequent to muscle damage (Wehling et al. 2001; Wehling-Henricks et al. 2005). Analyses of dystrophic mice bred to express a nNOS transgene in muscle demonstrate decreases in macrophage activity, and circulating levels of muscle enzymes, indicative of reduced muscle degeneration (Wehling et al. 2001; Nguyen and Tidball 2003b), as well as improvements in neuromuscular junction organization (Shiao et al. 2004). Comparatively little has been established concerning the use of vector-based NOS expression in muscles, although it is exciting to consider that such an approach could potentially recapitulate the elevated expression of NOS in a postnatal intervention strategy. Recent developments in dystrophin expression cassette design have established a configuration that can restore NOS expression levels in dystrophic muscles subsequent to dystrophin expression (Lai et al. 2009). However, a coadministration approach to elicit increased NOS levels may yet prove even more effective in managing pathological aspects of severe dystrophies, including those where NOS levels are not reduced as a result of the primary defect.

Also of interest as a strategy to reduce local inflammation and metabolic stress within muscles, is the attenuation of tumor necrosis factor (TNF) levels. In dystrophic muscles featuring ongoing muscle degeneration, increased TNF levels are thought to negatively affect muscle structure and function by several mechanisms (Grounds et al. 2008). Most prominent of these is the role of TNF to contribute to elevated inflammatory cell accumulation and activity, with the aforementioned consequences for increased breakdown of myofibers (Hodgetts et al. 2006). However, TNF (and other proinflammatory cytokines) are increasingly being regarded as potential negative regulators of signal transduction events that are associated with the control of protein synthesis and breakdown within myofibers themselves (Grounds et al. 2008). Thus TNF is gaining more attention as a prominent player in the pathology of degenerative dystrophic states. Dystrophic mice cross-bred with TNF-knockout animals have been shown to exhibit reduced evidence of local inflammation, with a consequent improvement in muscle morphology and function (Gosselin et al. 2003). These data have supported investigations into intervention-based strategies to reduce TNF levels. Based on initial findings in other forms of inflammatory diseases, several studies have reported encouraging evidence of reduced inflammation and myofiber/ myofibril necrosis in mouse models of muscular dystrophy following the administration of either TNF-specific antibodies or doses of soluble TNF receptor (Hodgetts et al. 2006; Pierno et al. 2007; Radley et al. 2008). These interventions have established the potential for benefit in controlling TNF levels but utilize systemically circulating agents that could conceivably exert nonmuscle effects as well. With regards to a genetic approach that might sustainably reduce TNF levels in skeletal muscles in a constrained fashion, less has been accomplished presently. Other groups have developed recombinant viral vectors that express soluble TNF receptor subunits for the prospective treatment of inflammatory conditions, with promising early outcomes (Sandalon et al. 2007). These approaches could be adapted for the treatment of muscular dystrophies, whereby a muscle-selective vector platform carrying a TNF receptor expression cassette under the control of a regulatable muscle-specific transcriptional promoter/ enhancer configuration could afford controlled muscle-localized expression.

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