“mdx” Mouse myopathy: Histopathological, morphometric and histochemical observations on young mice

Geissinger, H. D.; Rao, P. V. V. Prasada; McDonald-Taylor, C.K.

doi:10.1016/s0021-9975(08)80015-1

Cited by 12 publications

(8 citation statements)

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“…We have shown that the mdx mouse model of DMD shows greater uptake of [ 99m Tc]MDP in muscle, particularly in the quadriceps and diaphragm, as compared with the controls. This agrees with histological reports of muscle calcification in mdx mice [8], the well-known target of diphosphonates to hydroxyapatite calcium deposits [15], and prior clinical observations of [ 99m Tc]MDP accumulation in injured or dystrophic skeletal muscle [16,26,27]. These results were consistent and reproducible across sites and cohorts, demonstrating that [ 99m Tc]MDP SPECT in mdx mice can be used as a reliable multi-site imaging assay to track muscle injury.…”

Section: Discussionsupporting

confidence: 87%

“…The myopathic phenotype starts around 3 weeks with muscle necrosis and some visible muscle weakness. The structure of neuromuscular junctions in mdx mice is also altered and by approximately 4 weeks of age, there is evidence of mild fibrosis and phagocytosis of necrotic muscle tissue [5][6][7] as well as degenerative lesions with calcification [7,8]. Several medical imaging approaches have been used to assess a variety of diseaserelated processes in dystrophic mouse models, including changes in muscle architecture [7], sarcolemmal permeability [9], cardiac metabolic differences [10], and skeletal muscle degeneration and regeneration [11].…”

Section: Introductionmentioning

confidence: 99%

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SPECT Imaging of Muscle Injury with [99mTc]MDP in a Mouse Model of Muscular Dystrophy

et al. 2019

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Purpose: Tc-99m methylene diphosphonate ([ 99m Tc]MDP) is an in vivo bone imaging agent that also accumulates in injured skeletal muscle cells. The objective of this study was to investigate if [ 99m Tc]MDP could be used to detect muscle injury in the mdx mouse model of Duchenne muscular dystrophy (DMD). Procedures: Static whole-body single-photon emission computed tomography/computed tomography (CT) scans were acquired at 2 h post-injection of [ 99m Tc]MDP in two cohorts of animals at different sites: one cohort of mice at 6, 15, and 19 weeks of age, and a separate cohort at 16 weeks. The second cohort was also imaged with high-resolution CT at 8 weeks. Results: mdx mice had higher [ 99m Tc]MDP uptake and significantly higher [ 99m Tc]MDP concentrations in muscle than controls. Conclusions: Higher uptake of [ 99m Tc]MDP in muscle of mdx mice agrees with histological reports of muscle calcification in mdx mice, and suggests the potential translational use of [ 99m Tc]MDP imaging for tracking DMD progression and therapeutic response.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

SPECT Imaging of Muscle Injury with [99mTc]MDP in a Mouse Model of Muscular Dystrophy

et al. 2019

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“…Although observed often in skeletal muscle of dystrophic mdx mice, 18 ectopic calcification has not been noted in the heart muscle of muscular dystrophy animal models. The calcification process has been most extensively studied in relation to the development of atherosclerotic plaques.…”

Section: Expression Of Regulators Of a Calcification Programmentioning

confidence: 95%

Combined Deficiency of Dystrophin and β1 Integrin in the Cardiac Myocyte Causes Myocardial Dysfunction, Fibrosis and Calcification

Elsherif

Huang

Shai

et al. 2008

Circulation Research

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Abstract-The dystrophin-glycoprotein complex is a large complex of membrane-associated proteins linking the cytoskeleton to the extracellular matrix in muscle. Transmembrane heterodimeric (␣␤) integrins serve also as cellular adhesion molecules and mechanotransducers. In the animal model for Duchenne muscular dystrophy, the mdx mouse, loss of dystrophin causes more severe abnormalities in skeletal than in cardiac muscle. We hypothesized that ablation of cardiac myocyte integrins in the mdx background would lead to a severe cardiomyopathic phenotype. Mdx mice were crossed to ones with cardiac myocyte-specific deletion of ␤1 integrin (␤1KO) to generate ␤1KOmdx. Unstressed ␤1KOmdx mice were viable and had normal cardiac function; however, high mortality was seen in peri-and postpartum females by 6 months of age, when severe myocardial necrosis and fibrosis and extensive dystrophic calcification was seen. Decreased ventricular function and blunted adrenergic responsiveness was found in the ␤1KOmdx mice compared with control (Lox/Lox, no Cre), ␤1KO, and mdx. Similarly, adult ␤1KOmdx males were more prone to isoproterenol-induced heart failure and death compared with control groups. Given the extensive calcification, we analyzed transcript levels of genes linked to fibrosis and calcification and found matrix ␥-carboxyglutamic acid protein, decorin, periostin, and the osteoblast transcription factor Runx2/Cbfa1 significantly increased in ␤1KOmdx cardiac muscle. Our data show that combined deficiency of dystrophin and integrins in murine cardiac myocytes results in more severe cardiomyopathic changes in the stressed myocardium than reduction of either dystrophin or integrins alone and predisposes to myocardial calcification. Key Words: Integrin Ⅲ muscular dystrophy Ⅲ dystrophin Ⅲ heart failure Ⅲ calcification T he cardiac myocyte cytoskeleton and contractile apparatus are tethered to the sarcolemma at specialized regions termed costameres, which are aligned with the Z-disk. 1 Costameres are important for lateral force transmission from the sarcomere to the extracellular matrix (ECM) and from 1 myocyte to the next. 2 Three different cytoskeleton networks comprise the costamere: the dystrophin glycoprotein complex (DGC), the integrins, and the spectrinbased cytoskeleton.The DGC is composed of several membrane-spanning and associated proteins and is enriched in, but not restricted to, costameric regions. 2,3 In muscle, the DGC includes dystrophin, sarcoglycans (␣, ␤, ␥, ␦, , and ), dystroglycans (␣ and ␤), ␣-dystrobrevin, syntrophins (␣1, ␤1 and ␤2), sarcospan, and NO synthase. Dystrophin is a 427-kDa protein that constitutes a core component of the DGC. Mutations in the human dystrophin gene lead to Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, and X-linked dilated cardiomyopathy. 4 In mice, an X-linked recessive mutation in the dystrophin gene (mdx) results in loss of dystrophin expression, destabilization of the DGC, and muscular dystrophy. Whereas cardiomyopathy may occur early in the life of patie...

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“…Calcification of the skeletal muscles in mdx mice and dystrophic dogs has also been reported (Geissinger et al, 1990;Nguyen et al, 2002), although its mechanisms remain entirely unclear. Calcification of cardiovascular tissue has been especially well studied for its clinical consequences, as vascular calcification in dialysis patients is associated with morbidity and mortality (Ketteler et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Ectopic Calcification is Caused by Elevated Levels of Serum Inorganic Phosphate in Mdx Mice

Kikkawa

Ohno

Nagata

et al. 2009

Cell Struct. Funct.

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ABSTRACT. Ectopic calcification occurs in the skeletal muscle of mdx mice, a dystrophin-deficient animal model of Duchenne muscular dystrophy. The purpose of this study was to clarify the mechanism of the calcification. The calcified deposits were identified as hydroxyapatite, a crystallized form of calcium phosphate, and the serum inorganic phosphate (Pi) level in the mdx mice was approximately 1.4 times higher than that in the normal B10 mice, suggesting that Pi plays a critical role in the ectopic calcification. When C2C12 mouse myoblasts were cultured under high-Pi conditions, myogenic differentiation was retarded while the expression of osteogenic markers such as osteocalcin and Runx2 were upregulated. This was followed by the generation of calcium deposition. Moreover, ectopic calcification reduced to an undetectable level in most of the mdx mice fed a Pireduced diet. We therefore conclude that the Pi-induced osteogenesis of muscle cells is responsible for ectopic calcification in the skeletal muscle of mdx mice.

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“mdx” Mouse myopathy: Histopathological, morphometric and histochemical observations on young mice

Cited by 12 publications

References 7 publications

SPECT Imaging of Muscle Injury with [99mTc]MDP in a Mouse Model of Muscular Dystrophy

SPECT Imaging of Muscle Injury with [99mTc]MDP in a Mouse Model of Muscular Dystrophy

Combined Deficiency of Dystrophin and β1 Integrin in the Cardiac Myocyte Causes Myocardial Dysfunction, Fibrosis and Calcification

Ectopic Calcification is Caused by Elevated Levels of Serum Inorganic Phosphate in Mdx Mice

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