Mdx respiratory impairment following fibrosis of the diaphragm

Ishizaki, Masatoshi; Suga, Tomohiro; Kimura, En; Shiota, Tetsuya; Kawano, Ryoko; Uchida, Yuji; Uchino, Katsuhisa; Maeda, Yasushi; Uchino, Makoto

doi:10.1016/j.nmd.2008.02.002

Cited by 66 publications

(81 citation statements)

References 27 publications

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“…The mechanism underlying the increased right ventricular fibrosis is not clear; the size and shapes of the lesions suggest the fibrotic replacement of damaged cardiac myocytes. This is consistent with a model where the respiratory dysfunction of the mdx mouse (30,32,44) results in hypoventilation and increased constriction of the pulmonary vessels. This increase in afterload on the right ventricle has the potential to increase membrane damage and myocyte loss within this ventricle, as has been documented in the left ventricle where increases in afterload result in substantial increases in myocyte damage (18,34).…”

Section: Discussionsupporting

confidence: 91%

“…The increased right ventricular fibrosis may result from increased afterload following either sympathetic activation or hypoxia-induced constriction of the pulmonary artery secondary to hypoventilation. The latter of these two is supported by the severely dystrophic diaphragm in old mdx mice (12) and the already compromised respiratory function of the young mdx mouse (30,32,43,44). Together these observations indicate that respiratory insufficiency occurs in the mdx mouse and is progressive in nature.…”

Section: Discussionmentioning

confidence: 79%

“…Of all the skeletal muscles in the mdx mouse, the diaphragm shows the most significant levels of fibrosis and degeneration (61). This pathology translates into a progressive reduction in respiratory function in the mdx mouse, with dysfunction present as early as 3 mo of age (30,32,44). This chronic respiratory insufficiency of the mdx mouse makes this model particularly valuable for examining how respiratory dysfunction interacts with the dystrophic heart.…”

mentioning

confidence: 99%

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Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart

Meyers

Townsend

2015

American Journal of Physiology-Heart and Circulatory Physiology

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Duchenne muscular dystrophy (DMD) is a progressive disease of striated muscle deterioration. Respiratory and cardiac muscle dysfunction are particularly clinically relevant because they result in the leading causes of death in DMD patients. Despite the clinical and physiological significance of these systems, little has been done to understand the cardiorespiratory interaction in DMD. We show here that prior to the onset of global cardiac dysfunction, dystrophin-deficient mdx mice have increased cardiac fibrosis with the right ventricle being particularly affected. Using a novel biventricular cardiac catheterization technique coupled with cardiac stress testing, we demonstrate that both the right and left ventricles have significant reductions in both systolic and diastolic function in response to dobutamine. Unstimulated cardiac function is relatively normal except for a significant reduction in the ventricular pressure transient duration compared with controls. These biventricular analyses also reveal the absence of a dobutamine-induced increase in isovolumic relaxation in the right ventricle of control hearts. Simultaneous assessment of biventricular pressure demonstrates a dobutamine-dependent enhancement of coupling between the ventricles in control mice, which is absent in mdx mice. Furthermore, studies probing the passive-extension properties of the left ventricle demonstrate that the mdx heart is significantly more compliant compared with age-matched C57BL/10 hearts, which have an age-dependent stiffening that is completely absent from dystrophic hearts. These new results indicate that right ventricular fibrosis is an early indicator of the development of dystrophic cardiomyopathy, suggesting a mechanism by which respiratory insufficiency may accelerate the development of heart failure in DMD.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

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Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart

Meyers

Townsend

2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…The diaphragm muscle has been analyzed extensively in studies associated with the mdx (dystrophin-null) mouse, a murine model of Duchenne muscular dystrophy (Faulkner et al 2008;Mizunoya et al 2011). Compared to other muscles in the mdx mouse, the diaphragm shows earlier signs of the pathology with measurable muscle degeneration and fibrosis (Stedman et al 1991;Ishizaki et al 2008). It was reported that both costal and crural domains displayed pathological features in the mdx diaphragm, but there is only limited information specific to muscle domain comparison (Anderson et al 1998).…”

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confidence: 99%

A Contemporary Atlas of the Mouse Diaphragm

Stuelsatz

Keire

Almuly

et al. 2012

J Histochem Cytochem.

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The thoracic diaphragm is a unique skeletal muscle composed of costal, crural, and central tendon domains. Although commonly described in medical textbooks, newer insights into the diaphragm cell composition are scarce. Here, using reporter mice, combined with gene expression analyses of whole tissues and primary cultures, we compared the diaphragm domains and their myogenic progenitors (i.e., Pax3/7 satellite cells). The outcomes of these analyses underscore the similarities between the myogenic aspects of the costal and crural domains. Expression levels of all myogenic genes examined (except Pax3) were strongly affected in mdx (dystrophin-null) mice and accompanied by an increase in fibrosis- and adiposity-related gene expression. Cell culture studies further indicated the presence of a non-myogenic Pax3-expressing population, potentially related to vascular mural cells. We additionally investigated the diaphragm vasculature. XLacZ4 and Sca1-GFP transgenes allowed a fine definition of the arterial and microvasculature network based on reporter expression in mural cells and capillary endothelium, respectively. We also provide insights into the organization of the diaphragm venous system, especially apparent in the central tendon and exhibiting arcades lined with fat-containing cells. The novel information in this “contemporary atlas” can be further explored in the context of diaphragm pathology and genetic disorders.

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“…Although the mouse phenotype is milder than human DMD, there is a reduction in lifespan, thought to be due to respiratory or cardiac failure 11. In fact, the diaphragm is abnormal in both structure and function, making it a natural tissue to assess when testing DMD therapies 12, 13…”

mentioning

confidence: 99%

Anisomycin Activates Utrophin Upregulation Through a p38 Signaling Pathway

Hadwen

Farooq

Witherspoon

et al. 2018

Clinical Translational Sci

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Duchenne muscular dystrophy is a recessive X‐linked disease characterized by progressive muscle wasting; cardiac or respiratory failure causes death in most patients by the third decade. The disease is caused by mutations in the dystrophin gene that lead to a loss of functional dystrophin protein. Although there are currently few treatments for Duchenne muscular dystrophy, previous reports have shown that upregulating the dystrophin paralog utrophin in Duchenne muscular dystrophy mouse models is a promising therapeutic strategy. We conducted in silico mining of the Connectivity Map database for utrophin‐inducing agents, identifying the p38‐activating antibiotic anisomycin. Treatments of C2C12, undifferentiated murine myoblasts, and mdx primary myoblasts with anisomycin conferred increases in utrophin protein levels through p38 pathway activation. Anisomycin also induced utrophin protein levels in the diaphragm of mdx mice. Our study shows that repositioning small molecules such as anisomycin may prove to have Duchenne muscular dystrophy clinical utility.

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Mdx respiratory impairment following fibrosis of the diaphragm

Cited by 66 publications

References 27 publications

Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart

Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart

A Contemporary Atlas of the Mouse Diaphragm

Anisomycin Activates Utrophin Upregulation Through a p38 Signaling Pathway

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