scholarly journals Reduced plasticity and microtubule densification in muscular dystrophy-related cardiomyopathy

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Yuki Katanosaka
Keyword(s):  
Heart Failure ◽  
Muscular Dystrophy ◽  
Cardiac Dysfunction ◽  
Developmental Stages ◽  
Myocardial Dysfunction ◽  
Colchicine Treatment ◽  
Contractile Dysfunction ◽  
Causative Gene ◽  
Hypertrophic Response ◽  
Deficient Mice

The dystrophin–glycoprotein complex (DGC) links the intracellular cytoskeleton to the extracellular basement membrane, thereby providing structural support for the sarcolemma. Many patients with muscular dystrophies, particularly those with defects in cardiomyopathies with chamber dilation and myocardial dysfunction. Heart failure is the major cause of death for muscular dystrophy patients; however, the molecular pathomechanism remains unknown. Here, I show the detailed molecular pathogenesis of muscular dystrophy–associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced the glycosylation of α-dystroglycan and the expression of DGC proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that the physiological contribution of DGC proteins in the heart increases after 6 mo of age. In addition, Fktn-deficient mice maintain normal cardiac function at young age, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. Young Fktn-deficient mice did not show a compensative hypertrophic response to hemodynamic stress and quickly developed heart failure with chamber dilation and contractile dysfunction. In these mice, Ca2+-calcineurin signaling was already elevated under physiological conditions, and MEF2-HDAC axes essential for the hypertrophic response were unable to function under stress conditions. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi–microtubule networks, which were ameliorated with colchicine treatment. Microarray analysis in control and Fktn-deficient hearts suggest that elimination of Fktn impacts the expression profile of Golgi-related genes, and that the pathological mechanism of cardiac dysfunction induced by Fktn elimination partly overlaps with that of neurodegenerative disease. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and, thus, the results may lead to strategies for intervention.

scholarly journals Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yoshihiro Ujihara ◽  
Motoi Kanagawa ◽  
Satoshi Mohri ◽  
Satomi Takatsu ◽  
Kazuhiro Kobayashi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Muscular Dystrophy ◽  
Cardiac Dysfunction ◽  
Developmental Stages ◽  
Colchicine Treatment ◽  
Causative Gene ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Microtubule Networks ◽  
Molecular Pathomechanisms

AbstractHeart failure is the major cause of death for muscular dystrophy patients, however, the molecular pathomechanism remains unknown. Here, we show the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced α-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi-microtubule networks, which were ameliorated with colchicine treatment. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and thus, the results may lead to strategies for therapeutic intervention.

Bone marrow-derived cells contribute to contractile dysfunction in endotoxic shock

2005 ◽  
Vol 288 (2) ◽  
pp. H577-H583 ◽  
Author(s):  
Brian W. Binck ◽  
May F. Tsen ◽  
Miguel Islas ◽  
D. Jean White ◽  
Roger A. Schultz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Ex Vivo ◽  
Myocardial Dysfunction ◽  
Endotoxic Shock ◽  
Left Ventricular ◽  
Mouse Strains ◽  
Contractile Dysfunction ◽  
Contractile Responses ◽  
Bone Marrow Derived Cells ◽  
Deficient Mice

How infection precipitates depressed contractility is incompletely understood but may involve the immune, nervous, and endocrine systems as well as the heart itself. In this study, we examined the role of Toll-like receptor 4 (TLR4) in LPS-induced myocardial contractile depression. Eighteen hours following endotoxin challenge, we compared contractile responses in hearts from wild-type (WT) and TLR4-deficient mice using modified Langendorff preparations. Unlike hearts from WT mice, TLR4-deficient hearts did not reveal significant contractile dysfunction following LPS administration, as measured by decreased responses in maximal left ventricular pressure, +dP/d tmax, and −dP/d tmaxin ex vivo Langendorff preparations. These findings indicate a requirement for TLR4 in LPS-induced contractile depression. To determine the contribution of bone marrow-derived TLR4 function to LPS-induced myocardial dysfunction, we generated TLR4 chimeras using adoptive transfer between histocompatible mouse strains: either TLR4-deficient mice with TLR4+/+ bone marrow-derived cells or TLR4+/+ animals lacking TLR4 in their hematopoietic cells. We then compared the contractile responses of engrafted animals after LPS challenges. Engraftment of TLR4-deficient mice with WT marrow restored sensitivity to the myocardial depressant effects of LPS in TLR4-deficient hearts ( P < 0.05). Inactivation of bone marrow-derived TLR4 function, via transplantation of WT mice with TLR4−/− marrow, however, did not protect against the depressant effect of endotoxin. These findings indicate that bone marrow-derived TLR4 activity is sufficient to confer sensitivity to mice lacking TLR4 in all other tissues. However, because inactivation of marrow-derived TLR4 function alone does not protect against endotoxin-triggered contractile dysfunction, TLR4 function in other tissues may also contribute to this response.

Cardiomyocyte-specific loss of RNA polymerase II subunit 5-mediating protein causes myocardial dysfunction and heart failure

2018 ◽  
Vol 115 (11) ◽  
pp. 1617-1628
Author(s):  
Jian Zhang ◽  
Jingyi Sheng ◽  
Liwei Dong ◽  
Yinli Xu ◽  
Liming Yu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Genome Stability ◽  
Transforming Growth Factor ◽  
Myocardial Dysfunction ◽  
Transforming Growth Factor Β ◽  
And Function ◽  
Deficient Mice

AbstractAimsMyocardial dysfunction is an important cause of heart failure (HF). RNA polymerase II subunit 5 (RPB5)-mediating protein (RMP) is a transcriptional mediating protein which co-ordinates cellular processes including gene expression, metabolism, proliferation, and genome stability. However, its role in cardiac disease remains unknown. We aimed to determine the role and regulatory mechanisms of RMP in cardiomyocyte function and the development of HF.Methods and resultsMyocardial RMP expression was examined in human heart tissues from healthy controls and patients with advanced HF. Compared to normal cardiac tissues, RMP levels were significantly decreased in the myocardium of patients with advanced HF. To investigate the role of RMP in cardiac function, Cre-loxP recombinase technology was used to generate tamoxifen-inducible cardiomyocyte-specific Rmp knockout mice. Unexpectedly, cardiomyocyte-specific deletion of Rmp in mice resulted in contractile dysfunction, cardiac dilatation, and fibrosis. Furthermore, the lifespan of cardiac-specific Rmp-deficient mice was significantly shortened when compared with littermates. Mechanistically, we found that chronic HF in Rmp-deficient mice was associated with impaired mitochondrial structure and function, which may be mediated via a transforming growth factor-β/Smad3-proliferator-activated receptor coactivator1α (PGC1α)-dependent mechanism. PGC1α overexpression partially rescued chronic HF in cardiomyocyte-specific Rmp-deficient mice, and Smad3 blockade protected against the loss of PGC1α and adenosine triphosphate content that was induced by silencing RMP in vitro.ConclusionsRMP plays a protective role in chronic HF. RMP may protect cardiomyocytes from injury by maintaining PGC1α-dependent mitochondrial biogenesis and function. The results from this study suggest that RMP may be a potential therapeutic agent for treating HF.

scholarly journals Acute heart failure and bradyarrhythmia in a young male—what hides beneath the surface?: a case report

2021 ◽  
Author(s):  
João Santos ◽  
Inês Almeida ◽  
Inês Pires ◽  
Filipe Blanco
Keyword(s):  
Heart Failure ◽  
Muscular Dystrophy ◽  
Acute Heart Failure ◽  
De Novo ◽  
Muscular Atrophy ◽  
Myocardial Dysfunction ◽  
Young Male ◽  
Adult Age ◽  
Cardiac Symptoms ◽  
Ventricular Response

Abstract Background Muscular dystrophies are characterized by early onset muscular atrophy and weakness, with frequent cardiac involvement. Myocardial dysfunction and conduction system involvement are often rapidly progressive despite medical and device therapy, and may even precede muscular symptoms, posing a challenge to diagnosis. Case summary We report a case of a young male admitted to a cardiac intensive care unit due to “de novo” acute heart failure and atrial flutter with a slow ventricular response. Careful evaluation of past medical history revealed presence of neuromuscular symptoms since childhood, disregarded throughout adult age. Diagnostic workup allowed to establish a diagnosis of non-dilated hypokinetic cardiomyopathy secondary to Emery-Dreifuss muscular dystrophy, due to Lamin A/C gene mutation. Our patient was treated with neurohormonal modulation therapy and a CRT-D was implanted, but due to worsening advanced heart failure, cardiac transplantation was needed. Discussion Association of skeletal muscle and cardiac symptoms should always raise the suspicion for an underlying muscular dystrophy, since the consequences of a missed diagnosis are often dramatic. A timely diagnosis is crucial to prevent sudden death due to arrythmias in these patients and to delay the progressive course of cardiomyopathy.

scholarly journals Adenosine regulation of microtubule dynamics in cardiac hypertrophy

2009 ◽  
Vol 297 (2) ◽  
pp. H523-H532 ◽  
Author(s):  
John T. Fassett ◽  
Xin Xu ◽  
Xinli Hu ◽  
Guangshuo Zhu ◽  
Joel French ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Colchicine Treatment ◽  
Microtubule Dynamics ◽  
Protective Effects ◽  
Wild Type ◽  
Extracellular Adenosine

There is evidence that endogenous extracellular adenosine reduces cardiac hypertrophy and heart failure in mice subjected to chronic pressure overload, but the mechanism by which adenosine exerts these protective effects is unknown. Here, we identified a novel role for adenosine in regulation of the cardiac microtubule cytoskeleton that may contribute to its beneficial effects in the overloaded heart. In neonatal cardiomyocytes, phenylephrine promoted hypertrophy and reorganization of the cytoskeleton, which included accumulation of sarcomeric proteins, microtubules, and desmin. Treatment with adenosine or the stable adenosine analog 2-chloroadenosine, which decreased hypertrophy, specifically reduced accumulation of microtubules. In hypertrophied cardiomyocytes, 2-chloroadenosine or adenosine treatment preferentially targeted stabilized microtubules (containing detyrosinated α-tubulin). Consistent with a role for endogenous adenosine in reducing microtubule stability, levels of detyrosinated microtubules were elevated in hearts of CD73 knockout mice (deficient in extracellular adenosine production) compared with wild-type mice (195%, P < 0.05). In response to aortic banding, microtubules increased in hearts of wild-type mice; this increase was exaggerated in CD73 knockout mice, with significantly greater amounts of tubulin partitioning into the cold-stable Triton-insoluble fractions. The levels of this stable cytoskeletal fraction of tubulin correlated strongly with the degree of heart failure. In agreement with a role for microtubule stabilization in promoting cardiac dysfunction, colchicine treatment of aortic-banded mice reduced hypertrophy and improved cardiac function compared with saline-treated controls. These results indicate that microtubules contribute to cardiac dysfunction and identify, for the first time, a role for adenosine in regulating cardiomyocyte microtubule dynamics.

Abstract 11750: Inactivation of Cardiac Foxo1 by Insulin Signaling is Required for Cardiac Function and Suppression of β-Myosin Heavy Chain Gene Expression

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yajuan Qi ◽  
Yuxin Wu ◽  
Candice Thomas ◽  
Rajesh Kumar ◽  
Kenneth M Baker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Heart Failure ◽  
Insulin Resistance ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Insulin Signaling ◽  
Cardiac Dysfunction ◽  
Myocardial Dysfunction ◽  
Foxo1 Gene

Heart failure is a leading cause of morbidity and mortality in the USA and is closely associated with diabetes mellitus. The molecular link between diabetes and heart failure is incompletely understood. We recently demonstrated that insulin receptor substrate 1, 2 (IRS1, 2) are key components of insulin signaling and their dysfunction mediates insulin resistance, resulting in metabolic dysregulation and heart failure. Loss of IRS1 and IRS2 is associated with downstream Akt inactivation and in turn activation of the forkhead transcription factor Foxo1. To determine the role of Foxo1 in control of heart failure in insulin resistance and diabetes, we generated mice lacking Foxo1 gene specifically in the heart. Mice lacking both IRS1 and IRS2 in adult hearts exhibited severe heart failure and a remarkable increase in the β-isoform of myosin heavy chain (β-MHC) gene expression, while deletion of cardiac Foxo1 gene largely prevented the heart failure and resulted in a decrease in β-MHC expression. The effect of Foxo1 deficiency on rescuing cardiac dysfunction was also observed in db/db mice and high-fat diet (HFD) mice. Using cultures of primary ventricular cardiomyocytes, we found that Foxo1 interacts with the promoter region of β-MHC and stimulates gene expression, mediating an effect of insulin that suppresses β-MHC expression. Taken together, our study suggests that Foxo1 has important roles in promoting diabetic cardiomyopathy and controls β-MHC expression in development of cardiac dysfunction. Targeting Foxo1 and its regulation will provide novel strategies in preventing metabolic and myocardial dysfunction and influencing MHC plasticity in diabetes mellitus.

Abstract 361: Inactivation of Cardiac Foxo1 by Insulin Signaling Is Required for Cardiac Function and Suppression of β-Myosin Heavy Chain Gene Expression

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Yajuan Qi ◽  
Qinglei Zhu ◽  
Kebin Zhang ◽  
Candice Thomas ◽  
Rajesh Kumar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Heart Failure ◽  
Insulin Resistance ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Insulin Signaling ◽  
Cardiac Dysfunction ◽  
Myocardial Dysfunction ◽  
Foxo1 Gene

Heart failure is a leading cause of morbidity and mortality in the USA and is closely associated with diabetes mellitus. The molecular link between diabetes and heart failure is incompletely understood. We recently demonstrated that insulin receptor substrate 1, 2 (IRS1, 2) are key components of insulin signaling and their dysfunction mediates insulin resistance, resulting in metabolic dysregulation and heart failure. Loss of IRS1 and IRS2 is associated with downstream Akt inactivation and in turn activation of the forkhead transcription factor Foxo1. To determine the role of Foxo1 in control of heart failure in insulin resistance and diabetes, we generated mice lacking Foxo1 gene specifically in the heart. Mice lacking both IRS1 and IRS2 in adult hearts exhibited severe heart failure, loss of mitochondria, and a remarkable increase in the β-isoform of myosin heavy chain (β-MHC) gene expression, while deletion of cardiac Foxo1 gene largely prevented the heart failure and the loss of mitochondria, and resulted in a decrease in β-MHC expression. The effect of Foxo1 deficiency on rescuing cardiac dysfunction was also observed in db/db mice and high-fat diet (HFD) mice. Using cultures of primary ventricular cardiomyocytes, we found that Foxo1 interacts with the promoter region of β-MHC and stimulates gene expression, mediating an effect of insulin that suppresses β-MHC expression. Taken together, our study suggests that Foxo1 has important roles in promoting diabetic cardiomyopathy and controls β-MHC expression in development of cardiac dysfunction. Targeting Foxo1 and its regulation will provide novel strategies in preventing metabolic and myocardial dysfunction and influencing MHC plasticity in diabetes mellitus.

Ayurvedic management of Ducchen’s Muscular Dystrophy - A Case report

2017 ◽  
Vol 2 (4) ◽  
Author(s):  
Jayaraj R. ◽  
Veena G. Rao ◽  
Jyothi Nagalikar
Keyword(s):  
Muscular Dystrophy ◽  
Cardiac Dysfunction ◽  
Muscle Wasting ◽  
Progressive Disease ◽  
Genetic Disorder ◽  
Dystrophin Gene ◽  
Wasting Disease ◽  
Number Of Patients ◽  
Choice Of Treatment ◽  
Muscle Wasting Disease

Ducchen’s muscular dystrophy is most common X-linked recessive disorder affecting 30 in 100,000 live male births. The primary cause of this disease is mutations in Dystrophin gene which is essential for the structural and functional integrity of muscle. It is a progressive muscle wasting disease in which patients frequently develop contractures and lose the ability to walk between 6 and 12 years of age. With progressive disease most patients succumb to death from respiratory failure and cardiac dysfunction in their twenties. As this is a genetic disorder we can consider it as Adibala Pravritta Vyadhi. As Mamsa Kshaya is seen at some muscles and Mamsa Vriddhi at other this is an Avarana Vata Vyadhi. In both Upsthambha and Nirupasthmbha Vatavyadhi, Basthi is considered as prime choice of treatment. A Variety of Ksheerabasti in the form of Kalabasti is studied in this condition by taking subjective and objective parameters. As this has given better improvement with no adverse effects in the patient, it can be tried in large number of patients.

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