Dysferlin Deficiency and the Development of Cardiomyopathy in a Mouse Model of Limb-Girdle Muscular Dystrophy 2B

Chase, Thomas H.; Cox, Gregory A.; Burzenski, Lisa M.; Foreman, Oded; Shultz, Leonard D.

doi:10.2353/ajpath.2009.080930

Cited by 53 publications

(60 citation statements)

References 20 publications

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“…Consequently, it does not surprise that dysferlindeficiency is linked to cardiomyopathy development in mice [4,7,9] and in LGMD2B patients [7,8]. Whereas dilated cardiomyopathy in the context of dystrophin-deficiency was associated with substantial cardiac voltage-dependent ion channel abnormalities [10][11][12][13], here we report basically normal ion channel properties in dysferlin-deficient (dysf) cardiomyocytes.…”

Section: Discussionmentioning

confidence: 78%

“…Hence two important conclusions A reasonable explanation for the lack of ion channel abnormalities in dysferlin-as opposed to dystrophin-deficient cardiomyocytes observed in the present study is yet to be found. A conspicuous difference between dysferlin- [4,9,31] and dystrophin-deficient [32][33][34][35][36] dystrophic mice is that the latter develop a more severe dilated cardiomyopathy. It is therefore tempting to speculate that the incidence of considerable cardiac electrophysiological abnormalities in a dystrophy mouse model is associated with the severity of the developing dilated cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

“…Besides the relatively well characterized skeletal muscle degenerative processes, it has more recently become apparent that dysferlin deficiency is also associated with cardiac complications. Thus, both in LGMD2B patients [7,8] and dysferlin-deficient mouse models [4,7,9] the development of a dilated cardiomyopathy was observed.…”

Section: Introductionmentioning

confidence: 99%

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Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes

Rubi

Gawali

Kubista

et al. 2015

Cell Physiol Biochem

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Background/Aims: Dysferlin plays a decisive role in calcium-dependent membrane repair in myocytes. Mutations in the encoding DYSF gene cause a number of myopathies, e.g. limb-girdle muscular dystrophy type 2B (LGMD2B). Besides skeletal muscle degenerative processes, dysferlin deficiency is also associated with cardiac complications. Thus, both LGMD2B patients and dysferlin-deficient mice develop a dilated cardiomyopathy. We and others have recently reported that dystrophin-deficient ventricular cardiomyocytes from mouse models of Duchenne muscular dystrophy show significant abnormalities in voltage-dependent ion channels, which may contribute to the pathophysiology in dystrophic cardiomyopathy. The aim of the present study was to investigate if dysferlin, like dystrophin, is a regulator of cardiac ion channels. Methods and Results: By using the whole cell patch-clamp technique, we compared the properties of voltage-dependent calcium and sodium channels, as well as action potentials in ventricular cardiomyocytes isolated from the hearts of normal and dysferlin-deficient (dysf) mice. In contrast to dystrophin deficiency, the lack of dysferlin did not impair the ion channel properties and left action potential parameters unaltered. In connection with normal ECGs in dysf mice these results suggest that dysferlin deficiency does not perturb cardiac electrophysiology. Conclusion: Our study demonstrates that dysferlin does not regulate cardiac voltage-dependent ion channels, and implies that abnormalities in cardiac ion channels are not a universal characteristic of all muscular dystrophy types.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes

Rubi

Gawali

Kubista

et al. 2015

Cell Physiol Biochem

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“…Dysferlin is a 230-kDa membrane inserted protein with binding affinity to both calcium and phospholipid (44), which is enriched in subsarcolemma vesicles and can be quickly recruited to the membrane injury site (7) to facilitate membrane repair (54). In cardiomyocytes, dysferlin is found to be present in both sarcolemma t-tubules and intercalated discs (30). For t-tubule membrane repair, it has been proposed that upon insult, dysferlin can be recruited to t-tubules along with its interacting partners including BIN1, caveolin-3, and EHDs to induce repair (46).…”

Section: Costamere Complex and T-tubule Membraneassociated Scaffoldsmentioning

confidence: 99%

Cardiac T-Tubule Microanatomy and Function

Hong

Shaw

2017

Physiological Reviews

151

125

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Unique to striated muscle cells, transverse tubules (t-tubules) are membrane organelles that consist of sarcolemma penetrating into the myocyte interior, forming a highly branched and interconnected network. Mature t-tubule networks are found in mammalian ventricular cardiomyocytes, with the transverse components of t-tubules occurring near sarcomeric z-discs. Cardiac t-tubules contain membrane microdomains enriched with ion channels and signaling molecules. The microdomains serve as key signaling hubs in regulation of cardiomyocyte function. Dyad microdomains formed at the junctional contact between t-tubule membrane and neighboring sarcoplasmic reticulum are critical in calcium signaling and excitation-contraction coupling necessary for beat-to-beat heart contraction. In this review, we provide an overview of the current knowledge in gross morphology and structure, membrane and protein composition, and function of the cardiac t-tubule network. We also review in detail current knowledge on the formation of functional membrane subdomains within t-tubules, with a particular focus on the cardiac dyad microdomain. Lastly, we discuss the dynamic nature of t-tubules including membrane turnover, trafficking of transmembrane proteins, and the life cycles of membrane subdomains such as the cardiac BIN1-microdomain, as well as t-tubule remodeling and alteration in diseased hearts. Understanding cardiac t-tubule biology in normal and failing hearts is providing novel diagnostic and therapeutic opportunities to better treat patients with failing hearts.

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“…Mutations in the dysferlin gene lead to several types of musclewasting diseases denoted as dysferlinopathies -limb-girdle muscular dystrophy type 2B (LGMD2B) (1,2), Miyoshi myopathy (MM) (2), and a distal anterior compartment myopathy (DACM) (3). Dysferlinopathies have also been shown to be associated with a late-onset dilative cardiomyopathy (4)(5)(6). Dysferlin is a 230-kDa protein that is widely expressed in different tissues and cells including striated muscle (7) and immune cells (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice

Han¹,

Frett²,

Levy³

et al. 2010

J. Clin. Invest.

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Mutations in the dysferlin gene underlie a group of autosomal recessive muscle-wasting disorders denoted as dysferlinopathies. Dysferlin has been shown to play roles in muscle membrane repair and muscle regeneration, both of which require vesicle-membrane fusion. However, the mechanism by which muscle becomes dystrophic in these disorders remains poorly understood. Although muscle inflammation is widely recognized in dysferlinopathy and dysferlin is expressed in immune cells, the contribution of the immune system to the pathology of dysferlinopathy remains to be fully explored. Here, we show that the complement system plays an important role in muscle pathology in dysferlinopathy. Dysferlin deficiency led to increased expression of complement factors in muscle, while muscle-specific transgenic expression of dysferlin normalized the expression of complement factors and eliminated the dystrophic phenotype present in dysferlin-null mice. Furthermore, genetic disruption of the central component (C3) of the complement system ameliorated muscle pathology in dysferlin-deficient mice but had no significant beneficial effect in a genetically distinct model of muscular dystrophy, mdx mice. These results demonstrate that complement-mediated muscle injury is central to the pathogenesis of dysferlinopathy and suggest that targeting the complement system might serve as a therapeutic approach for this disease.

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Dysferlin Deficiency and the Development of Cardiomyopathy in a Mouse Model of Limb-Girdle Muscular Dystrophy 2B

Cited by 53 publications

References 20 publications

Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes

Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes

Cardiac T-Tubule Microanatomy and Function

Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice

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