scholarly journals TRF2 rescues pathogenic phenotypes in Duchenne muscular dystrophy cardiomyocytes derived from human iPSCs

2022 ◽  
Author(s):  
Asuka Eguchi ◽  
Sofía I. Torres-Bigio ◽  
Kassie Koleckar ◽  
Foster Birnbaum ◽  
Helen M. Blau
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Cell Size ◽  
Mechanical Load ◽  
Nuclear Size ◽  
Calcium Handling ◽  
Healthy Controls ◽  
Telomere Attrition ◽  
Human Ipscs

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Heart failure, driven by cardiomyocyte death, fibrosis, and the development of dilated cardiomyopathy, is the leading cause of death in DMD patients. Current treatments decrease the mechanical load on the heart; however, these treatments do not address the root cause of dilated cardiomyopathy: cardiomyocyte death. Previously, we showed that longer telomeres are protective against dilated cardiomyopathy. Here we investigated the role of telomeres as a target for therapy in DMD cardiomyocytes using human induced pluripotent stem cells (iPSCs) to model the disease. Compared to healthy controls, DMD cardiomyocytes exhibited reduced telomere lengths, cell size, nuclear size, and sarcomere density. The telomere-binding protein, TRF2, is a core component of the shelterin complex, which protects chromosome ends. TRF2 levels are reduced relative to healthy controls in DMD cardiomyocytes. We hypothesized that decreased TRF2 drives telomere attrition and subsequent cardiomyocyte death in the progression of dilated cardiomyopathy. Our data show that TRF2 overexpression prevented telomere attrition and also rescued deficits in cell size, nuclear size, sarcomere density, and calcium handling. These data highlight the benefits of TRF2 upregulation as a potential gene therapy to delay the onset of dilated cardiomyopathy.

scholarly journals Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies

2020 ◽  
Vol 9 (2) ◽  
pp. 520 ◽  
Author(s):  
Michelle L. Law ◽  
Houda Cohen ◽  
Ashley A. Martin ◽  
Addeli Bez Batti Angulski ◽  
Joseph M. Metzger
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Cardiac Myocyte ◽  
Contractile Function ◽  
Cytosolic Calcium ◽  
Therapeutic Strategies ◽  
Calcium Handling ◽  
Cardiac Contractile Function ◽  
Mechanistic Basis

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults with DMD, manifesting as dilated cardiomyopathy (DCM) in the later stages of disease. Sarcolemmal instability, leading to calcium mishandling and overload in the cardiac myocyte, is a key mechanistic contributor to muscle cell death, fibrosis, and diminished cardiac contractile function in DMD patients. Current therapies for DMD cardiomyopathy can slow disease progression, but they do not directly target aberrant calcium handling and calcium overload. Experimental therapeutic targets that address calcium mishandling and overload include membrane stabilization, inhibition of stretch-activated channels, ryanodine receptor stabilization, and augmentation of calcium cycling via modulation of the Serca2a/phospholamban (PLN) complex or cytosolic calcium buffering. This paper addresses what is known about the mechanistic basis of calcium mishandling in DCM, with a focus on DMD cardiomyopathy. Additionally, we discuss currently utilized therapies for DMD cardiomyopathy, and review experimental therapeutic strategies targeting the calcium handling defects in DCM and DMD cardiomyopathy.

A carrier of Duchenne muscular dystrophy with dilated cardiomyopathy but no skeletal muscle symptom

1995 ◽  
Vol 17 (3) ◽  
pp. 202-205 ◽  
Author(s):  
Hirotoshi Kinoshita ◽  
Yu-ichi Goto ◽  
Mitsuru Ishikawa ◽  
Tetsuya Uemura ◽  
Kouichi Matsumoto ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Muscle Symptom

Effect of Ivabradine in dilated cardiomyopathy from Duchenne muscular dystrophy: A chance for slowing progression of heart failure?

2016 ◽  
Vol 223 ◽  
pp. 286-288 ◽  
Author(s):  
Giuseppina De Benedittis ◽  
Giulia Della Rosa ◽  
Enzo D'Ettorre ◽  
Prisco Piscitelli ◽  
Alessandro Distante ◽  
...  
Keyword(s):  
Heart Failure ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy

Ifetroban Reduces Coronary Artery Dysfunction in a Mouse Model of Duchenne Muscular Dystrophy

2021 ◽  
Author(s):  
Ray Mitchell ◽  
Norman E Frederick ◽  
Emily R Holzman ◽  
Francesca Agobe ◽  
Heather C M Allaway ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Cardiac Function ◽  
Dilated Cardiomyopathy ◽  
Coronary Arteries ◽  
Oral Treatment ◽  
Mdx Mice ◽  
Muscarinic Agonist ◽  
Therapeutic Implications

Dilated cardiomyopathy contributes to morbidity and mortality in Duchenne Muscular Dystrophy (DMD), an inheritable muscle wasting disease caused by a mutation in the dystrophin gene. Preclinical studies in mouse models of muscular dystrophy have demonstrated reduced cardiomyopathy and improved cardiac function following oral treatment with the potent and selective thromboxane A2/prostanoid receptor (TPr) antagonist, ifetroban. Further, a phase 2 clinical trial (NCT03340675, Cumberland Pharmaceutical) is currently recruiting subjects to determine if ifetroban can improve cardiac function in patients with DMD. Although TPr is a promising therapeutic target for the treatment of dilated cardiomyopathy in DMD, little is known about TPr function in coronary arteries that perfuse blood through the cardiac tissue. In the current study, isolated coronary arteries from young (~3-5 months) and aged (~9-12 months) mdx mice, a widely used mouse model of DMD, and age-matched controls were examined using wire myography. Vasoconstriction to increasing concentrations of TPr agonist U-46619(U4) was enhanced in young mdx mice versus controls. Additionally, young mdx mice displayed a significant attenuation in endothelial cell-mediated vasodilation to increasing concentrations of the muscarinic agonist acetylcholine (ACh). Since TPr activation was enhanced in young mdx mice, U4-mediated vasoconstriction was measured in the absence and presence of ifetroban. Ifetroban reduced U4-mediated vasoconstriction in young mdx and both aged mdx and control mice. Overall, our data demonstrate enhanced coronary arterial vasoconstriction to TPr activation in young mdx mice, a phenotype that could be reversed with ifetroban. These data could have important therapeutic implications for improving cardiovascular function in DMD.

scholarly journals Single SERCA2a Therapy Ameliorated Dilated Cardiomyopathy for 18 Months in a Mouse Model of Duchenne Muscular Dystrophy

2020 ◽  
Vol 28 (3) ◽  
pp. 845-854 ◽  
Author(s):  
Nalinda B. Wasala ◽  
Yongping Yue ◽  
William Lostal ◽  
Lakmini P. Wasala ◽  
Nandita Niranjan ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Dilated Cardiomyopathy

scholarly journals Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle

2002 ◽  
Vol 82 (2) ◽  
pp. 291-329 ◽  
Author(s):  
Derek J. Blake ◽  
Andrew Weir ◽  
Sarah E. Newey ◽  
Kay E. Davies
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Protein Complex ◽  
Muscle Disease ◽  
Calcium Handling ◽  
Dystrophic Muscle ◽  
Gene Encoding ◽  
Muscle Wasting Disease ◽  
Novel Therapeutic Strategies ◽  
Related Proteins

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and α-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.

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