Various forms of muscular dystrophies frequently exhibit increased susceptibility to fatigue during repeated recruitment/contraction (Frascarelli et al. 1988; Wineinger et al. 1998). Reduced fatigue resistance may be a consequence of the reduced number of functional fibers present within a given muscle being tasked with a comparatively greater work requirement compared with the myofiber/myofibril population in a non dystrophic muscle, although increased inflammatory cell activity and altered metabolic status also appear to contribute to this deleterious phenotype. Therefore, intervention strategies with the potential to reduce the susceptibility of muscles to fatigue could be valuable in increasing/sustaining muscle function. One component of muscle fatigue is the role of oxidative stress upon ATP production. As mentioned earlier, supplementation of muscle NO levels via increased expression of NOS could be a viable approach to enhance fatigue resistance. Several groups have shown that nNOS deficient mice (dystrophic and otherwise) exhibit reduced force-producing capacity with repeated contraction (Kobayashi et al. 2008; Percival et al. 2008). Possible mechanisms by which increased NOS expression may reduce fatigue relate to cGMP stimulated mitochondrial biogenesis (in the longer term), and also through enhancing cGMP-based signaling that contributes to the vasomodulation of the muscle's circulatory system (Nisoli et al. 2003, 2004; Kobayashi et al. 2008). That pharmacological restoration of cGMP-mediated signaling can counter the increased susceptibility to fatigue observed in dystrophic muscles supports this argument, and serves as justification for further investigation into the potential to ameliorate fatigue susceptibility in dystrophic muscles via interventions that can increase NOS expression (Kobayashi et al. 2008).
Interestingly, although IGF-I has been traditionally regarded as a promoter of skeletal muscle hypertrophy, several studies have observed that IGF-I based interventions can also increase the oxidative metabolism of dystrophic muscles, and increase contractile capacity over the course of a repetitive recruitment test (Gregorevic et al. 2004; Schertzer et al. 2006). The mechanisms associated with this effect of IGF-I expression remain a point of continued investigation, but reflect the complexity of biological effects exerted by a single factor depending on its mode of administration. Improving fatigue resistance of existing muscle cells by using combined IGF and NOS therapy would also have the beneficial consequences of improving aspects of muscle strength, and reducing oxidative stress and inflammation, thereby highlighting the potential of codelivery based strategies.
A different intervention that could enhance the abilities of muscles to sustain contractile capacity with repeated exertion may be based around the cellular mechanisms influenced by the expression and activation of the peroxisome proliferator activated receptor (PPAR) family of transcription regulators. Of the various PPAR isoforms, PPAR-delta is particularly strongly expressed in the skeletal muscle, and especially in the more fatigue-resistant and oxidative metabolism-favoring type I fiber population (Wang et al. 2004). PPAR-delta null mice have been shown to exhibit reductions in oxidative metabolism which correlate with decreased running performance in a treadmill-based assay (Wang et al. 2004). Transgenic mice expressing an activated PPAR-delta construct, and animals administered a PPAR-delta activating agonist have been shown to demonstrate varying degrees of increasingly induced gene expression associated with a "fast-to-slow" muscle fiber type transformation which encompasses increased oxidative metabolism and importantly, considerably improved fatigue resistance under exercise (Wang et al. 2004; Narkar et al. 2008). Animals that express increased levels of the PPAR coactivator peroxisomes-proliferator-activated receptor-gamma coactivator 1 alpha (PGC1-alpha)-1a have also been shown to exhibit increased fatigue resistance attributes, further substantiating the importance of the PPAR-associated mechanisms as key regulators of metabolism and muscle fiber phenotype (Lin et al. 2002; Handschin et al. 2007a). So potent are some of the adaptations observed following stimulation of the PPAR-mediated processes, that it has been proposed that PPAR-delta agonist interventions may even be able to impart some of the benefits of regular endurance exercise without the need for the exercise component itself (Narkar et al. 2008). Such a statement should be qualified by acknowledging that exercise adaptations affect multiple organs as well as the nerve-vasculature-tendon-muscle interactions, though it is plausible to suggest that at least a degree of functional benefit could be derived via an intervention designed to increase the activation of PPAR-delta in the muscles of dystrophic mice and patients. Further investigation is required to explore this fascinating possibility, and also the prospects of further enhancing muscle function by combining interventions that could enhance fatigue resistance.
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