Progression of dystrophic features and activation of mitogen‐activated protein kinases and calcineurin by physical exercise, in hearts of <i>mdx</i> mice

Nakamura, Akinori; Yoshida, Katsumi; Takeda, Shin’ichi; Dohi, Naoko; Ikeda, Shu‐ichi

doi:10.1016/s0014-5793(02)02739-4

Cited by 82 publications

(73 citation statements)

References 40 publications

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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

136

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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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

136

133

View full text Add to dashboard Cite

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“…In support of this view, in myotonic mouse muscles, in which membrane hyperexcitability is triggered by a loss-offunction mutation of ClC-1 channel, a fast-to-slow transition results from activity and calcium-dependent activation of muscle-specific transcription factors, such as MEF-2 (Wu and Olson, 2002). Interestingly, these pathways, also involved in regeneration and/or apoptosis, are activated by exercise in heart of mdx animals (Nakamura et al, 2002). Thus, the understanding of the molecular mechanisms underlying the acute drop of gCl can help the identification of early therapies.…”

Section: Experimental Conditions Drugs In Vitromentioning

confidence: 91%

Enhanced Dystrophic Progression in mdx Mice by Exercise and Beneficial Effects of Taurine and Insulin-Like Growth Factor-1

Pierno²,

Liantonio³

et al. 2003

J Pharmacol Exp Ther

183

283

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A preclinical screening for prompt-to-use drugs that are safer than steroids and beneficial in Duchenne muscular dystrophy was performed. Compounds able to reduce calcium-induced degeneration (taurine or creatine 10% in chow) or to stimulate regeneration [insulin-like growth factor-1 (IGF-1); 50 or 500 g/kg s.c.] were administered for 4 to 8 weeks to mdx mice undergoing chronic exercise on a treadmill, a protocol to worsen dystrophy progression. ␣-Methyl-prednisolone (PDN; 1 mg/kg) was used as positive control. The effects were evaluated in vivo on forelimb strength and in vitro electrophysiologically on the macroscopic chloride conductance (gCl), an index of degeneration-regeneration events in mdx muscles, and on the mechanical threshold, a calcium-sensitive index of excitation-contraction coupling. The exercise produced a significant weakness and an impairment of gCl, by further decreasing the already low value of degenerating diaphragm (DIA) and fully hampering the increase of gCl typical of regenerating extensor digitorum longus (EDL) mdx muscle. The already negative voltage threshold for contraction of mdx EDL was also slightly worsened. Taurine Ͼ creatine Ͼ IGF-1 counteracted the exercise-induced weakness. The amelioration of gCl was drug-and muscle-specific: taurine was effective in EDL, but not in DIA muscle; IGF-1 and PDN were fully restorative in both muscles, whereas creatine was ineffective. An acute effect of IGF-1 on gCl was observed in vitro in untreated, but not in IGF-1-treated exercised mdx muscles. Taurine Ͼ PDN Ͼ IGF-1, but not creatine, significantly ameliorated the negative threshold voltage values of the EDL fibers. The results predict a potential benefit of taurine and IGF-1 for treating human dystrophy.

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“…A similar exercise protocol exacerbates myocardial histopathology in mdx mice that lack the cytoskeletal protein, dystrophin. 16 This regimen proved to be initially more difficult for Lmna ϩ/Ϫ mice; however, exercise performance improved with training (Online Table IV). There were no differences in apoptosis between sedentary and trained WT and Lmna ϩ/Ϫ mice ( Figure 3B and Online Table V).…”

Section: Effects Of Exercise Trainingmentioning

confidence: 99%

Effects of Mechanical Stress and Carvedilol in Lamin A/C–Deficient Dilated Cardiomyopathy

Chandar¹,

Yeo²,

Leimena³

et al. 2010

Circulation Research

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Rationale: Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking. Objective: Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna ؉/؊ ) mice. Methods and Results: Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna ؉/؊ mice develop adult-onset DCM with relatively more severe disease in males. Lmna ؉/؊ cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna ؉/؊ mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna ؉/؊ mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna ؉/؊ mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna ؉/؊ mice from 12 to 40 weeks with the ␤-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice. Conclusions: These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts. (Circ Res. 2010;106:573-582.)Key Words: familial dilated cardiomyopathy Ⅲ lamin A/C Ⅲ mechanical stress Ⅲ exercise Ⅲ carvedilol M utations in the LMNA gene that encodes the nuclear lamina proteins lamin A and lamin C are the most common cause of familial dilated cardiomyopathy (DCM) identified to date, 1 accounting for 5% to 10% familial DCM overall and 30% to 45% families with DCM and conduction system disease (CD). [2][3][4][5] Affected individuals frequently have a rapidly progressive downhill clinical course, requiring pacemaker implantation or heart transplantation, with an increased risk of sudden death. [2][3][4][5] Despite the clinical importance of LMNA mutations, very little is known about mechanisms of disease pathogenesis and strategies to prevent DCM have not been investigated.Because one-third of DCM-causing LMNA mutations are stop codons, splice site variants or insertions/deletions that reduce lamin A/C protein levels, 1,5 Lmna knockout mice are a useful and clinically relevant model to study DCM mechanisms. 6 We have previously reported that homozygous Lmna knockout (Lmna Ϫ/Ϫ ) mice exhibit severe DCM by 4 to 6 weeks. 7 Heterozygous Lmna knockout (Lmna ϩ/Ϫ ) mice show ...

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Progression of dystrophic features and activation of mitogen‐activated protein kinases and calcineurin by physical exercise, in hearts of mdx mice

Cited by 82 publications

References 40 publications

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

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

Enhanced Dystrophic Progression in mdx Mice by Exercise and Beneficial Effects of Taurine and Insulin-Like Growth Factor-1

Effects of Mechanical Stress and Carvedilol in Lamin A/C–Deficient Dilated Cardiomyopathy

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