scholarly journals Chloroquine Decreases Cardiomyocyte Autophagy and Improves Cardiac Function in a Mouse Model of Duchenne Muscular Dystrophy

2021 ◽  
Author(s):  
Takaya Hirata ◽  
Shiro Baba ◽  
Kentaro Akagi ◽  
Daisuke Yoshinaga ◽  
Katsutsugu Umeda ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Left Ventricular ◽  
Muscle Disease ◽  
Therapeutic Modality ◽  
Cardiomyocyte Autophagy ◽  
And Function ◽  
Ventricle Size

Abstract Background: Duchenne muscular dystrophy (DMD), a severe degenerative skeletal and cardiac muscle disease, has a poor prognosis, and no curative treatments are available. Because autophagy has been reported to contribute to skeletal muscle degeneration, therapies targeting autophagy are expected to improve skeletal muscle hypofunction. However, the role of this regulatory mechanism has not been evaluated clearly in DMD cardiomyocytes. Methods: In the present study, we demonstrated that autophagy was enhanced in the cardiomyocytes of mdx mice, a model of DMD, and that increased autophagy contributed to the development of cardiomyopathy in this context. Results: As assessed by GFP-mRFP-LC3 transfection, autophagosomes were more abundant in cardiomyocytes of mdx mice compared with control wild-type (WT) mice. The number of autophagosomes was significantly enhanced by isoproterenol-induced cardiac stress (4 weeks) in cardiomyocytes of mdx but not WT mice. Simultaneously, isoproterenol increased cardiomyocyte fibrosis in mdx but not WT mice. Administration of chloroquine, an autophagy inhibitor, significantly decreased cardiomyocyte autophagy and fibrosis in mdx mice, even after isoproterenol treatment. Left ventricle size and function were evaluated by echocardiography. Left ventricular contraction was decreased in mdx mice after isoproterenol treatment compared with control mice, which was alleviated by chloroquine administration.Conclusions: These findings suggested that heart failure of DMD could be associated with autophagy. Therefore, autophagy inhibitors, such as chloroquine, are a potential therapeutic modality for heart failure in DMD patients.

Association between pulmonary function and left ventricular volume and function in duchenne muscular dystrophy

2019 ◽  
Vol 60 (3) ◽  
pp. 286-291 ◽  
Author(s):  
Arshjot Khokhar ◽  
Athira Nair ◽  
Vishal Midya ◽  
Ashutosh Kumar ◽  
Ankita Sinharoy ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Pulmonary Function ◽  
Left Ventricular Volume ◽  
Ventricular Volume ◽  
Left Ventricular ◽  
And Function

scholarly journals Multiomics Analysis of the mdx/mTR Mouse Model of Duchenne Muscular Dystrophy

2019 ◽  
Author(s):  
Douglas W Van Pelt ◽  
Yalda A Kharaz ◽  
Dylan C Sarver ◽  
Logan R Eckhardt ◽  
Justin T Dzierzawski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Metabolism ◽  
Muscle Disease ◽  
Protein Abundance ◽  
Pathological Changes ◽  
Hindlimb Muscles ◽  
Dystrophin Protein ◽  
Insight Into

AbstractDuchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by extensive muscle weakness. Patients with DMD lack a functional dystrophin protein, which transmits force and organizes the cytoskeleton of skeletal muscle. Multiomic studies evaluate combined changes in the transcriptome, proteome, and metabolome, and have been proposed as a way to obtain novel insight about disease processes from preclinical models. We therefore sought to use this approach to study pathological changes in dystrophic muscles. We evaluated hindlimb muscles of male mdx/mTR mice, which lack a functional dystrophin protein and have deficits in satellite cell abundance and proliferative capacity. Wild type (WT) C57BL/6J mice served as controls. Muscle fiber contractility was measured, along with changes in the transcriptome using RNA sequencing, and in the proteome, metabolome, and lipidome using mass spectroscopy. While mdx/mTR mice displayed gross pathological changes and continued cycles of degeneration and regeneration, we found no differences in fiber contractility between strains. However, there were numerous changes in the transcriptome and proteome related to protein balance, contractile elements, extracellular matrix, and metabolism. There was only a 53% agreement in fold change data between the proteome and transcriptome, highlighting the need to study protein abundance along with gene expression measures. Numerous changes in markers of skeletal muscle metabolism were observed, with dystrophic muscles exhibiting elevated glycolytic metabolites. These findings highlight the utility of multiomics in studying muscle disease, and provide additional insight into the pathological changes in dystrophic muscles that might help to guide evidence-based exercise prescription in DMD patients.

Abstract 279: A Deletion In The N2A Region Of Titin Carried By Muscular Dystrophy With Myositis (mdm) Mice Severely Affects Skeletal Muscle, But Not The Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Ida G Lunde ◽  
Hiroko Wakimoto ◽  
Michael A Burke ◽  
Wolfgang Linke ◽  
Geir Christensen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Cardiac Titin ◽  
Reduced Body ◽  
Region I ◽  
And Function

20% of dilated cardiomyopathy patients carry mutations in the giant protein titin. Mutations are predominant in A band but also occur in I band, a domain that regulates passive tension and myocyte signaling. A recessive mouse mutation in titin I band N2A region (mdm) causes early onset muscular dystrophy with myositis and death. We assessed cardiac morphology, function, and transcriptional profiles (RNAseq) in mdm mice. Young homozygous mdm mice (n>6) have reduced body weight (7gms) vs. heterozygous (20gm) or WT (17gm) littermates, with severe skeletal muscle dystrophy. Four-week old homozygous mdm mice have higher left ventricular (LV): body weight ratios. Echocardiography revealed thinner LV posterior wall and septum (LVPWd and IVSd) and normal LV diameter (LVDd); when normalized for body weight, cardiac dimensions were increased compared to WT or heterozygous mdm mice. Fractional shortening was reduced in homozygous Mdm mice (35%) vs. WT (40-41%, p<0.01); histology showed neither overt pathology nor fibrosis. Titin gels showed lack of difference in cardiac titin isoform pattern, consistent with RNAseq, which showed the mdm titin transcript excluded exons 107 and 108, deleting in frame 48 amino acids. 240 transcripts (0.8%) were differentially expressed (fold change >1.5 and <0.75, p<0.001) in homozygous vs. heterozygous mdm hearts; ANP and BNP were mildly upregulated (2- and 1.2-fold). Altered transcripts participated in extracellular and immune signaling pathways. Among titin binding partners, only calpain-3 that interacts with N2A was changed (0.6-fold), consistent with previous reports in skeletal muscle. As humans have heterozygous mutations, we stressed adult heterozygous mdm and WT mice (2 weeks of angiotensin II infusion): both had comparable hypertrophic responses (increased LVPWd and IVSd). Aged (89 week old) unstressed heterozygous mdm mice had normal cardiac dimensions and function. The N2A region, I-band titin mdm mutation causes minimal cardiac dysfunction in mice, unlike the severe skeletal muscle phenotype. Human I-band mutations are unlikely to cause dilated cardiomyopathy.

scholarly journals Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy

2017 ◽  
Vol 114 (50) ◽  
pp. E10763-E10771 ◽  
Author(s):  
Heaseung Sophia Chung ◽  
Grace E. Kim ◽  
Ronald J. Holewinski ◽  
Vidya Venkatraman ◽  
Guangshuo Zhu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Left Ventricular ◽  
Muscle Disease ◽  
Intracellular Ca ◽  
Transient Receptor ◽  
The Impact

Duchenne muscular dystrophy (DMD) is an X-linked disorder with dystrophin loss that results in skeletal and cardiac muscle weakening and early death. Loss of the dystrophin–sarcoglycan complex delocalizes nitric oxide synthase (NOS) to alter its signaling, and augments mechanosensitive intracellular Ca2+ influx. The latter has been coupled to hyperactivation of the nonselective cation channel, transient receptor potential canonical channel 6 (Trpc6), in isolated myocytes. As Ca2+ also activates NOS, we hypothesized that Trpc6 would help to mediate nitric oxide (NO) dysregulation and that this would be manifest in increased myocardial S-nitrosylation, a posttranslational modification increasingly implicated in neurodegenerative, inflammatory, and muscle disease. Using a recently developed dual-labeling proteomic strategy, we identified 1,276 S-nitrosylated cysteine residues [S-nitrosothiol (SNO)] on 491 proteins in resting hearts from a mouse model of DMD (dmdmdx:utrn+/−). These largely consisted of mitochondrial proteins, metabolic regulators, and sarcomeric proteins, with 80% of them also modified in wild type (WT). S-nitrosylation levels, however, were increased in DMD. Genetic deletion of Trpc6 in this model (dmdmdx:utrn+/−:trpc6−/−) reversed ∼70% of these changes. Trpc6 deletion also ameliorated left ventricular dilation, improved cardiac function, and tended to reduce fibrosis. Furthermore, under catecholamine stimulation, which also increases NO synthesis and intracellular Ca2+ along with cardiac workload, the hypernitrosylated state remained as it did at baseline. However, the impact of Trpc6 deletion on the SNO proteome became less marked. These findings reveal a role for Trpc6-mediated hypernitrosylation in dmdmdx:utrn+/− mice and support accumulating evidence that implicates nitrosative stress in cardiac and muscle disease.

scholarly journals Cytokines and Chemokines as Regulators of Skeletal Muscle Inflammation: Presenting the Case of Duchenne Muscular Dystrophy

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Boel De Paepe ◽  
Jan L. De Bleecker
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Current Knowledge ◽  
Damage Control ◽  
Inflammatory Cells ◽  
Muscle Disease ◽  
Fiber Damage ◽  
Cytokines And Chemokines ◽  
The Individual

Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary effects on muscle fiber damage control and tissue regeneration. In this review, current knowledge of cytokine and chemokine expression in Duchenne muscular dystrophy and its relevant animal disease models is listed, and implications for future therapeutic avenues are discussed.

scholarly journals Understanding the Process of Fibrosis in Duchenne Muscular Dystrophy

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Yacine Kharraz ◽  
Joana Guerra ◽  
Patrizia Pessina ◽  
Antonio L. Serrano ◽  
Pura Muñoz-Cánoves
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Inflammatory Cells ◽  
Dystrophin Gene ◽  
New Developments ◽  
Muscle Stem Cells ◽  
Muscle Fibrosis ◽  
Tissue Healing ◽  
And Function

Fibrosis is the aberrant deposition of extracellular matrix (ECM) components during tissue healing leading to loss of its architecture and function. Fibrotic diseases are often associated with chronic pathologies and occur in a large variety of vital organs and tissues, including skeletal muscle. In human muscle, fibrosis is most readily associated with the severe muscle wasting disorder Duchenne muscular dystrophy (DMD), caused by loss of dystrophin gene function. In DMD, skeletal muscle degenerates and is infiltrated by inflammatory cells and the functions of the muscle stem cells (satellite cells) become impeded and fibrogenic cells hyperproliferate and are overactivated, leading to the substitution of skeletal muscle with nonfunctional fibrotic tissue. Here, we review new developments in our understanding of the mechanisms leading to fibrosis in DMD and several recent advances towards reverting it, as potential treatments to attenuate disease progression.

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