Failure to Confirm a Vascular Cause of Muscular Dystrophy

Bradley, Walter G.; O'Brien, M D; Walder, D. N.; Murchison, Dorothy; Johnson, Margaret M.; Newell, D. J.

doi:10.1001/archneur.1975.00490490070007

Cited by 30 publications

(10 citation statements)

References 14 publications

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“…These findings are in agreement with the radioautography studies of Bradley et a1. 2 The increased capillary density in dystrophic muscle in conjunction with normal capillary diameter and red blood cell velocity (Table 1) indicate that total muscle blood flow is also incrcased in dystrophic muscle at. rest.…”

Section: Discussionmentioning

confidence: 97%

In vivo morphometric analysis of muscle microcirculation in dystrophic mice

1981

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In order to test the vascular hypothesis of muscular dystrophy, the gracilis muscle in 6- to 7-week-old C57BL/6J-dy2J normal and dystrophic mice was studied using in vivo quantitative morphometric techniques to determine the total length and surface area of capillaries in which blood was flowing per unit volume of muscle. Individual capillary lengths, diameters, and red blood cell velocities were also quantified. During resting conditions, the capillary density(length per unit volume of muscle) and surface area are increased significantly in dystrophic muscle compared to normal muscle. Under fully vasodilated conditions, the capillary density and surface area are similar in normal and dystrophic muscle. Individual capillary lengths, diameters, and red blood cell velocities are also similar in normal and dystrophic muscle under resting conditions. These results indicate that, contrary to the vascular hypothesis, dystrophic muscle at rest has increased capillary density, surface area, and blood flow. It is postulated that the increased capillary density in dystrophic muscle at rest is secondary to muscle fiber breakdown.

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Section: Discussionmentioning

confidence: 97%

In vivo morphometric analysis of muscle microcirculation in dystrophic mice

1981

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“…This vascular theory was based mainly on the histological observation in DMD patients of small random foci of muscle fibers in the same stage of degeneration or regeneration, and on the experimental reproduction in animals of these characteristic lesions by maneuvers that disrupted the microvasculature (30,31). However, subsequent morphological (32)(33)(34) and clinical studies (35,36) provided no definitive evidence in support of either structural or functional vascular abnormalities, although the clinical studies generally measured blood flows only under conditions of rest or during maximal vasodilation and interpretation of the results often was clouded by the lack of age-and strength-matched control subjects. Our present data together with recent data from three different dystrophic mouse models demonstrating vascular abnormalities (12,37,38) suggest that this vascular theory should be revisited.…”

Section: Discussionmentioning

confidence: 99%

Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy

Sander

Chavoshan

Harris

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

395

371

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Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutation of the gene encoding the cytoskeletal protein dystrophin. Despite a wealth of recent information about the molecular basis of DMD, effective treatment for this disease does not exist because the mechanism by which dystrophin deficiency produces the clinical phenotype is unknown. In both mouse and human skeletal muscle, dystrophin deficiency results in loss of neuronal nitric oxide synthase, which normally is localized to the sarcolemma as part of the dystrophin-glycoprotein complex. Recent studies in mice suggest that skeletal muscle-derived nitric oxide may play a key role in the regulation of blood flow within exercising skeletal muscle by blunting the vasoconstrictor response to ␣-adrenergic receptor activation. Here we report that this protective mechanism is defective in children with DMD, because the vasoconstrictor response (measured as a decrease in muscle oxygenation) to reflex sympathetic activation was not blunted during exercise of the dystrophic muscles. In contrast, this protective mechanism is intact in healthy children and those with polymyositis or limb-girdle muscular dystrophy, muscle diseases that do not result in loss of neuronal nitric oxide synthase. This clinical investigation suggests that unopposed sympathetic vasoconstriction in exercising human skeletal muscle may constitute a heretofore unappreciated vascular mechanism contributing to the pathogenesis of DMD.

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“…However, the functional ischemia associated with deficiencies in skeletal muscle NOS could clearly occur in the absence of any abnormalities in the vasculature. Other studies that did not support the vascular hypothesis were those that failed to demonstrate any clear changes of blood flow in the muscles of DMD patients (Bradley et al, 1975;Gudrun et al, 1975;Leinonen et al, 1979), but the types of local changes that occur due to NOS deficiency would have gone undetected in the earlier studies because of their low levels of sensitivity. When the elucidation of the genetic basis first of DMD and then other muscular dystrophies revealed biochemical abnormalities highly restricted to skeletal muscle cells, attention turned almost entirely to cell-intrinsic abnormalities of skeletal muscle.…”

Section: Does Displacement Of Nos From the Sarcolemma Cause Muscle Dementioning

confidence: 99%

Role of nitric oxide in the pathogenesis of muscular dystrophies: A “two hit” hypothesis of the cause of muscle necrosis

Rando

2001

Microscopy Res & Technique

123

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Although the genetic and biochemical bases of many of the muscular dystrophies have been elucidated, the pathophysiological mechanisms leading to muscle cell death and degeneration remain elusive. Among the most well studied of the dystrophies are those due to defects in proteins that make up the dystrophin-glycoprotein complex (DGC). There has been much interest in the role of nitric oxide (NO(*)) in the pathogenesis of these diseases because the enzyme that synthesizes NO(*), nitric oxide synthase (NOS), is associated with the DGC. Recent studies of dystrophies related to DGC defects suggest that one mechanism of cellular injury is functional ischemia related to alterations in cellular NOS and disruption of a normal protective action of NO(*). This protective action is the prevention of local ischemia during contraction-induced increases in sympathetic vasoconstriction. However, the loss of this protection, alone, does not explain the subsequent muscle cell death and degeneration since mice lacking neuronal NOS (the predominant isoform expressed in muscle) do not develop a muscular dystrophy. Thus, there must be additional biochemical changes conferred upon the cells by these DGC defects, and these changes are discussed in terms of a proposed "two hit" hypothesis of the pathogenetic mechanisms that underlie the muscular dystrophies. According to this hypothesis, pathogenic defects in the DGC have at least two biochemical consequences: a reduction in NO(*)-mediated protection against ischemia, and an increase in cellular susceptibility to metabolic stress. Either one alone may be insufficient to lead to muscle cell death. However, in combination, the biochemical consequences are sufficient to cause muscle degeneration. The role of oxidative stress as a final common pathophysiologic pathway is discussed in terms of data showing that oxidative injury precedes pathologic changes and that muscle cells with defects in the DGC have an increased susceptibility to oxidant challenges. Accordingly, this "two hit" hypothesis may explain many of the complex spatial and temporal variations in disease expression that characterize the muscular dystrophies, such as grouped necrosis, a pre-necrotic phase of the disease, and selective muscle involvement.

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Failure to Confirm a Vascular Cause of Muscular Dystrophy

Cited by 30 publications

References 14 publications

In vivo morphometric analysis of muscle microcirculation in dystrophic mice

In vivo morphometric analysis of muscle microcirculation in dystrophic mice

Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy

Role of nitric oxide in the pathogenesis of muscular dystrophies: A “two hit” hypothesis of the cause of muscle necrosis

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