Phenotype of dystrophinopathy in old <i>MDX</i> mice

Lefaucheur, Jean Pascal; Pastoret, Christian; Sebille, Alain

doi:10.1002/ar.1092420109

Cited by 190 publications

(165 citation statements)

References 27 publications

(32 reference statements)

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“…During the first few months, only small areas of fibrosis are noted in limb skeletal muscle of mdx mice. In contrast, increased connective tissue formation can be detected in skeletal and cardiac muscle of older mdx mice resembling the histopathological findings of patients with DMD (22,23). Our morphological analyses of aged hearts from mdx mice confirm the previous reports of increased fibrosis.…”

Section: Discussionsupporting

confidence: 89%

Myostatin does not regulate cardiac hypertrophy or fibrosis

Cohn

Liang

Shetty

et al. 2007

Neuromuscular Disorders

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Myostatin is a negative regulator of muscle growth. Loss of myostatin has been shown to cause increase in skeletal muscle size and improve skeletal muscle function and fibrosis in the dystrophindeficient mdx mouse, an animal model for Duchenne muscular dystrophy. We evaluated whether lack of myostatin has an impact on cardiac muscle growth and fibrosis in vivo. Using genetically modified mice we assessed whether myostatin absence induces similar beneficial effects on cardiac function and fibrosis. Cardiac mass and ejection fraction were measured in wild type, myostatin-null, mdx and double mutant mdx/myostatinnull mice by high resolution echocardiography. Heart mass, myocyte area and extent of cardiac fibrosis were determined post mortem. Myostatin-null mice do not demonstrate ventricular hypertrophy when compared to wild type mice as shown by echocardiography (ventricular mass 0.69± 0.01 g vs.0.69±0.018 g, P = 0.75, respectively) and morphometric analyses including heart/body weight ratio (5.39±0.45mg/g vs. 5.62±0.58mg/g, P = 0.59 respectively) and cardiomyocyte area 113.67±1.5μm 2 , 116.85±1.9μm 2 ; P = 0.2). Moreover, absence of myostatin does not attenuate cardiac fibrosis in the dystrophin deficient mdx mouse model for DMD (12.2% vs. 12% respectively, P = 0.88). The physiological role of myostatin in cardiac muscle appears significantly different than that in skeletal muscle as it does not induce cardiac hypertrophy and does not modulate cardiac fibrosis in mdx mice.

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Section: Discussionsupporting

confidence: 89%

Myostatin does not regulate cardiac hypertrophy or fibrosis

Cohn

Liang

Shetty

et al. 2007

Neuromuscular Disorders

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“…[32], [33], [34] Our histological results are in agreement with previous studies demonstrating patchy fibrosis in the ventricles of mdx mice. [15], [35], [36], [37], [38] The loss of functional muscle tissue and resulting fibrosis can lead to decreased cardiac systolic and diastolic function. Since the fibrosis is patchy and does not localize specifically to areas with the greatest muscle involvement, i.e.…”

Section: Discussionmentioning

confidence: 99%

Dystrophin-deficient cardiomyopathy in mouse: Expression of Nox4 and Lox are associated with fibrosis and altered functional parameters in the heart

Spurney

Knoblach

Pistilli

et al. 2008

Neuromuscular Disorders

137

133

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Duchenne muscular dystrophy (DMD; dystrophin-deficiency) causes dilated cardiomyopathy in the second decade of life in affected males. We studied the dystrophin-deficient mouse heart (mdx) using high frequency echocardiography, histomorphometry, and gene expression profiling. Heart dysfunction was prominent at 9-10 months of age and showed significantly increased LV internal diameter (end systole) and decreased posterior wall thickness. This cardiomyopathy was associated with a 30% decrease in shortening fraction. Histologically, there was a 10-fold increase in connective tissue volume (fibrosis). mRNA profiling with RT-PCR validation showed activation of key profibrotic genes, including Nox4 and Lox. The Nox gene family expression differed in mdx heart and skeletal muscle, where Nox2 was specifically induced in skeletal muscle while Nox4 was specifically induced in heart. This is the first report of an altered profibrotic gene expression profile in cardiac tissue of dystrophic mice showing echocardiographic evidence of cardiomyopathy.

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“…Fibre damage, either focal in trauma (Schultz et al, 1985) or induced by pathology that is intrinsic to fibres (Cooper, 1989;Hoffman et al, 1987;Kunkel and Hoffman, 1989;Lefaucheur et al, 1995) or extrinsic, e.g. ischemia (Authier et al, 1997; HansenSmith and Carlson, 1979;Makitie and Teravainen, 1977a;Makitie and Teravainen, 1977b), induces myogenic cells to become activated, proliferate and fuse to form new fibres that elongate between mature fibres.…”

Section: Skeletal Muscle Plasticitymentioning

confidence: 99%

The satellite cell as a companion in skeletal muscle plasticity:currency, conveyance, clue, connector and colander

Anderson

2006

Journal of Experimental Biology

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THE JOURNAL OF EXPERIMENTAL BIOLOGY 2277 Satellite cells in muscle plasticity formed cells fusing to form myoblasts and finally multinucleated muscle fibres.'That conference was a landmark in studies of the satellite cell and muscle regeneration, and was attended by many of the notable and pioneering contributors to the field of muscle development and muscle regeneration. Muir summarized the debate on a working definition of the satellite cell, as follows (Muir, 1970):'The satellite cell of striated muscle can be defined as a mononucleated cell, whose cytoplasm does not contain myofilaments, and which is enclosed by or lies within the basement membrane component of the sarcolemma of the striated muscle fibre. This definition does not exclude cells which are partially or completely separated from the muscle fibre plasma membrane by extensions of the basement membrane, providing that the basement membrane forms a complete investment of their outer surfaces. ' Although there were presentations detailing the observed uptake of 3 H-thymidine into nuclei of satellite cells (Hay, 1970), the role of satellite cells as precursors was not fully established in 1969. In fact there was still very strong debate that a muscle fibre could fragment into blastema cells that led to new formation of muscle. Even at this time, there was more than one paper on the appearance of osteogenic and chondrogenic tissues from minces of muscle replaced under the skin, and a report of muscle fibre nuclei contributed by a labelled connective tissue grafted into a salamander limb during regeneration (Steen, 1970).It wasn't until two seminal reports from the laboratory of Dr Charles Leblond at McGill University (Moss and Leblond, 1970;Moss and Leblond, 1971) that skeletal muscle satellite cells were convincingly identified as the source of precursor cells that proliferate and fuse to form new skeletal muscle fibres. Time-course studies of labelled nuclei in growing muscle showed that satellite cells were the only muscle cells that had incorporated 3 H-thymidine. The report followed work on colchicine-treated rats (MacConnachie et al., 1964) that showed mitotic figures only in the peripheral 'satellite' position on muscle fibres. The idea that muscle fibre nuclei give rise to the increasing number of myonuclei during the growth was convincingly ruled out (Enesco and Puddy, 1964). The notion that satellite cells contribute these domains to a growing or regenerating fibre, one at a time, is daunting in light of the expenditure of proliferative energy and fusion events. However, it speaks strongly to one of the major roles of satellite cells as a currency of muscle (see below). Satellite cells were also observed on intrafusal fibres (Katz, 1961). Two types of satellite cells were identified on these socalled muscle spindle fibres and were distinguished from those on extrafusal fibres (Maynard and Cooper, 1973), although at least one would now be called a myoblast.Although typically quiescent in normal adult muscle, satellite cells are generally con...

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Phenotype of dystrophinopathy in old MDX mice

Abstract: Late in life, mdx mice develop a muscular dystrophy close to DMD dystrophinopathy. We suggest that the study of the effects of ageing in mdx mice would give clues to better understand the pathophysiology of DMD.

Cited by 190 publications

References 27 publications

Myostatin does not regulate cardiac hypertrophy or fibrosis

Myostatin does not regulate cardiac hypertrophy or fibrosis

Dystrophin-deficient cardiomyopathy in mouse: Expression of Nox4 and Lox are associated with fibrosis and altered functional parameters in the heart

The satellite cell as a companion in skeletal muscle plasticity:currency, conveyance, clue, connector and colander

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