Duchenne Muscular Dystrophy: Functional Ischemia Reproduces Its Characteristic Lesions

Abstract

The highly characteristic early and midstage histological lesions of Duchenne dystrophy were reproduced experimentally in the rat by the combination of a vascular abnormality, aortic ligation, which does not affect the structure of the intramuscular blood vessels, and the humoral vasoactive substance 5-hydroxytryptamine. Neither ligation nor injection of 5-hydroxytryptamine alone causes changes in the muscle fibers. This result establishes the possibility of a similar combined mechanism for a nonstructural ischemia pathogenesis in Duchenne dystrophy. The proposed pathogenesis is contrary to the generally held idea that the cause is an intrinsic abnormality of muscle fiber metabolism.

Sarcolemmal Damage in Dystrophin Deficiency Is Modulated by Synergistic Interactions between Mechanical and Oxidative/Nitrosative Stresses

“…19,20,25 The levels of oxidative stress and muscle injury produced by I/R in our study are greater than would be expected to occur in the mdx mouse during normal muscle activity, and hence the magnitude of differential responses between dystrophic and wildtype mice could be amplified by our acute model. Nonetheless, our results suggest that increases in oxidative/ nitrosative stress triggered by I/R may greatly contribute to the mechanical damage suffered by dystrophin-deficient muscle fiber membranes.…”

“…23 Few data are available to support or refute the existence of a heightened susceptibility to oxidative stress-induced membrane damage in DMD patients, but it is interesting to note that transient limb ischemia of 10-minute duration followed by 1 minute of reperfusion caused increased serum creatine kinase levels in a group of DMD patients. 24 Ischemia/reperfusion (I/R) has been implicated in the pathogenesis of dystrophin deficiency as noted earlier 19,20,25 and is also a potent inducer of oxidative stress in muscle. 26 -29 In the present study, we hypothesized that dystrophin-deficient muscle could be abnormally susceptible to cellular damage induced by oxidative and nitrosative (NO-driven) modifications, which could in turn promote the hallmark increases in membrane fragility and mechanical stress-induced disruption of the sarcolemma.…”

Sarcolemmal nNOS anchoring reveals a qualitative difference between dystrophin and utrophin

“…Consequently, the protective vessel relaxation mechanism is compromised (Brenman et al, 1995;Chang et al, 1996;Lai et al, 2009;Sander et al, 2000;Thomas et al, 1998). In this regard, contraction-associated ischemic injury has been recognized as one of the earliest pathological changes in DMD muscle (Mendell et al, 1971;Parker and Mendell, 1974). The physiological relevance of membrane-associated nNOS was further emphasized by several recent reports (Kobayashi et al, 2008;Lai et al, 2009;Percival et al, 2008).…”

Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy

“…Despite the fact that dystrophin is missing in all myofibers, muscle disease does not occur simultaneously throughout the entire muscle. The characteristic early histopathology in DMD muscle closely resembles focal necrosis seen after functional ischemia (5,6). The identification of nNOS as a component of the dystrophin-associated glycoprotein complex (DGC) provides a molecular explanation for the unique muscle lesions in DMD (7,8).…”