Cardiac lesions in Duchenne muscular dystrophy model rats with out-of-frame            &lt;i&gt;Dmd&lt;/i&gt; gene mutation mediated by CRISPR/Cas9 system

Miyamoto, Mao; Tochinai, Ryota; Sekizawa, Shin-Ich; Shiga, Takanori; Uchida, Kazuyuki; Tsuru, Yoshiharu; Kuwahara, Masayoshi

doi:10.1293/tox.2020-0018

Cited by 4 publications

(9 citation statements)

References 28 publications

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“…In recent years, we have generated a rat model of DMD (DMD rats) using a CRISPR/Cas9 genome editing system. Our previous research showed that DMD rats exhibited more severe skeletal muscle damage and cardiomyopathy phenotypes than mdx mice 11 – 14 . In DMD rats, cardiac degeneration and fibrosis progress with age and overt left ventricular (LV) dysfunction occurs around 8–10 months old 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

A medium-chain triglyceride containing ketogenic diet exacerbates cardiomyopathy in a CRISPR/Cas9 gene-edited rat model with Duchenne muscular dystrophy

Fujikura

Kimura

Yamanouchi

et al. 2022

Sci Rep

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Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy caused by dystrophin mutations. Although respiratory management has improved the prognosis of patients with DMD, inevitable progressive cardiomyopathy is a current leading cause of premature death. Recently, we showed that a medium-chain triglyceride containing ketogenic diet (MCTKD) improves skeletal muscle function and pathology in a CRISPR/Cas9 gene-edited rat model with DMD. In this study, we sought to clarify whether MCTKD also improves the cardiomyopathy in these rats. DMD rats were fed either the MCTKD or normal diet (ND) from ages of 3 weeks to 9 months old. Compared with the ND-fed rats, MCTKD-fed rats showed significantly prolonged QRS duration, decreased left ventricular fractional shortening, an increased heart weight/body weight ratio, and progression of cardiac fibrosis. In contrast to our previous study which found that MCTKD improved skeletal myopathy, the current study showed unexpected exacerbation of the cardiomyopathy. Further studies are needed to explore the underlying mechanisms for these differences and to explore modified dietary options that improve skeletal and cardiac muscles simultaneously.

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Section: Introductionmentioning

confidence: 99%

A medium-chain triglyceride containing ketogenic diet exacerbates cardiomyopathy in a CRISPR/Cas9 gene-edited rat model with Duchenne muscular dystrophy

Fujikura

Kimura

Yamanouchi

et al. 2022

Sci Rep

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“…To confirm that Dm rats were deficient in dystrophin protein, soleus muscles from a WT or D m rat were immunostained with the dystrophin antibody previously used in our laboratory (supporting information Figure S3) (Miyamoto et al, 2020). Dystrophin is known to be expressed in the cerebral cortex, cerebellum, and hippocampus; however, little information regarding its expression in the brainstem is available.…”

Section: Resultsmentioning

confidence: 99%

“…The rat model showed pathological and pathophysiological changes in the heart in young adulthood, as commonly seen in human patients with DMD. For example, degeneration/necrosis of cardiomyocytes and myocardial fibrosis were prominent in the right ventricular wall and outer layer of the left ventricular wall at 3 months of age (Miyamoto et al, 2020). In addition, as background data, blood gas analysis revealed a low pH value (7.34) in D m rats, which suggested pathophysiological changes in the respiratory system.…”

Section: Introductionmentioning

confidence: 99%

Plasticity occurs in a specific phenotype of neurons in the nucleus tractus solitarius of dystrophin gene‐mutated rats

Chikamoto,

Tochinai,

Sekizawa

et al. 2023

Eur J of Neuroscience

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Duchenne muscular dystrophy (DMD) is a severe progressive neuromuscular disorder that causes cardiac and respiratory failure. Patients with DMD have tachycardia and autonomic nervous dysfunction at a young age, which can potentially worsen cardiorespiratory function. Therefore, we hypothesised that plasticity occurs in neurons of the cardiorespiratory brainstem nucleus (nucleus tractus solitarius [NTS]) due to DMD, thus affecting neuronal regulation because afferent information from cardiorespiratory organs changes with disease progression. Patch‐clamp experiments were performed on second‐order NTS neurons from Dmd‐mutated (Dm) rats that showed no functional dystrophin protein expression, as confirmed by immunohistochemistry. NTS neurons are classified into two electrophysiological phenotypes: one showing a delayed onset of spiking from hyperpolarised membrane potentials, namely, delayed‐onset spiking (DS)‐type neurons, and the other showing a rapid onset, namely, rapid‐onset spiking‐type neurons. Neuroplasticity mainly occurs in DS‐type neurons in Dm rats and is characterised by blunted neuronal excitability accompanied by reduced outward currents and a facilitatory effect on synaptic transmission, that is, an increased frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) without changes in the amplitude and an increased amplitude of tractus solitarius‐evoked EPSCs without changes in the paired‐pulse ratio. Although we cannot rule out the possibility that the neuroplastic changes observed in Dm rats were caused by dystrophin deficiency in the neurons themselves, the plasticity could be caused by cardiorespiratory deterioration and/or adaptation in DMD patients.

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“…These disease readouts were sufficient to include a therapeutic research arm, i.e., screening the efficiency of CRISPR/Cas9-mediated reframing or antisense oligo nucleotide (AON)-targeted exon skipping in all but one report [21]. Similar CRISPR/Cas9 approaches have been used to generate rat [26][27][28][29], rabbit [30] and non-human primate [31,32] models of dystrophinopathy that showed progressive heart involvement similar to those observed in humans.…”

Section: Genome-editing-based Models Of Dacmentioning

confidence: 99%

Multiomic Approaches to Uncover the Complexities of Dystrophin-Associated Cardiomyopathy

Gowran

Brioschi

Rovina

et al. 2021

IJMS

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Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling abilities. The reasons for the stunted progress in ameliorating dystrophin-associated cardiomyopathy (DAC) can be explained by the difficulties in detecting pathophysiological mechanisms which can also be efficiently targeted within the heart in the widest patient population. New perspectives are clearly required to effectively address the unanswered questions concerning the identification of authentic and effectual readouts of DAC occurrence and severity. A potential way forward to achieve further therapy breakthroughs lies in combining multiomic analysis with advanced preclinical precision models. This review presents the fundamental discoveries made using relevant models of DAC and how omics approaches have been incorporated to date.

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Cardiac lesions in Duchenne muscular dystrophy model rats with out-of-frame <i>Dmd</i> gene mutation mediated by CRISPR/Cas9 system

Abstract: Short running head Cardiac changes in Duchenne muscular dystrophy model rats

Cited by 4 publications

References 28 publications

A medium-chain triglyceride containing ketogenic diet exacerbates cardiomyopathy in a CRISPR/Cas9 gene-edited rat model with Duchenne muscular dystrophy

A medium-chain triglyceride containing ketogenic diet exacerbates cardiomyopathy in a CRISPR/Cas9 gene-edited rat model with Duchenne muscular dystrophy

Plasticity occurs in a specific phenotype of neurons in the nucleus tractus solitarius of dystrophin gene‐mutated rats

Multiomic Approaches to Uncover the Complexities of Dystrophin-Associated Cardiomyopathy

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