Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, δ-sarcoglycan, in hamster: An animal model of disrupted dystrophin-associated glycoprotein complex

Sakamoto, Aiji; Ono, Koji; Abe, Makoto; Jasmin, G.; Eki, Toshihiko; Murakami, Yasufumi; Masaki, Τοmoh; Toyo’oka, Toshimasa; Hanaoka, Fumio

doi:10.1073/pnas.94.25.13873

Cited by 281 publications

(242 citation statements)

References 27 publications

Supporting

Mentioning

229

Contrasting

Unclassified

Order By: Relevance

“…Analysis of skeletal muscle tissue biopsies from these patients reveals the loss or dramatic reductions in the expression of all the sarcoglycans when there is a disease-related mutation in a single sarcoglycan family member. The interdependence of sarcoglycan expression is also evident from studies employing sarcoglycan-null mouse models, although cardiac abnormalities are found in only ␤-, ␦-, and ␥-sarcoglycan-null mice (47)(48)(49)(50). Unlike these sarcoglycan-null mouse models, Cav-3 KO mice show no changes in expression or overall membrane localization of the sarcoglycans.…”

Section: Discussionmentioning

confidence: 78%

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Woodman

Park

Cohen

et al. 2002

Journal of Biological Chemistry

268

241

View full text Add to dashboard Cite

A growing body of evidence suggests that muscle cell caveolae may function as specialized membrane microdomains in which the dystrophin-glycoprotein complex and cellular signaling molecules reside. Caveolin-3 (Cav-3) is the only caveolin family member expressed in striated muscle cell types (cardiac and skeletal). Interestingly, skeletal muscle fibers from Cav-3 (؊/؊) knockout mice show a number of myopathic changes, consistent with a mild-to-moderate muscular dystrophy phenotype. However, it remains unknown whether a loss of Cav-3 affects the phenotypic behavior cardiac myocytes in vivo. Here, we present a detailed characterization of the hearts of Cav-3 knock-out mice. We show that these mice develop a progressive cardiomyopathic phenotype. At four months of age, Cav-3 knock-out hearts display significant hypertrophy, dilation, and reduced fractional shortening, as revealed by gated cardiac MRI and transthoracic echocardiography. Histological analysis reveals marked cardiac myocyte hypertrophy, with accompanying cellular infiltrates and progressive interstitial/peri-vascular fibrosis. Interestingly, loss of Cav-3 expression in the heart does not change the expression or the membrane association of the dystrophin-glycoprotein (DG) complex. However, a marker of the DG complex, ␣-sarcoglycan, was specifically excluded from lipid raft domains in the absence of Cav-3. Because activation of the Ras-p42/44 MAPK pathway in cardiac myocytes can drive cardiac hypertrophy, we next assessed the activation state of this pathway using a phospho-specific antibody probe. We show that p42/44 MAPK (ERK1/2) is hyperactivated in hearts derived from Cav-3 knock-out mice. These results are consistent with previous in vitro data demonstrating that caveolins may function as negative regulators of the p42/44 MAPK cascade. Taken together, our data argue that loss of Cav-3 expression is sufficient to induce a molecular program leading to cardiac myocyte hypertrophy and cardiomyopathy.

show abstract

Section: Discussionmentioning

confidence: 78%

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Woodman

Park

Cohen

et al. 2002

Journal of Biological Chemistry

268

241

View full text Add to dashboard Cite

show abstract

“…Recently, single gene defects that cause familial DCM (Ϸ25-30% of idiopathic DCM) have been identified for cytoskeletal (dystrophin, desmin, tafazzin, and ␦-sarcogycan) and sarcomeric (actin, tropomyosin, myosin, and troponin T) proteins (26,(39)(40)(41)(42)(43)(44)(45). Mutations in cytoskeletal proteins imply that deficits in transmission of force generated by sarcomere may be one mechanism for the pathogenesis of DCM.…”

Section: Discussionmentioning

confidence: 99%

Ca ²⁺ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

Morimoto

Harada

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

150

114

View full text Add to dashboard Cite

A deletion mutation ⌬K210 in cardiac troponin T (cTnT) was recently found to cause familial dilated cardiomyopathy (DCM). To explore the effect of this mutation on cardiac muscle contraction under physiological conditions, we determined the Ca 2؉ -activated force generation in permeabilized rabbit cardiac muscle fibers into which the mutant and wild-type cTnTs were incorporated by using our TnT exchange technique. The free Ca 2؉ concentrations required for the force generation were higher in the mutant cTnTexchanged fibers than in the wild-type cTnT-exchanged ones, with no statistically significant differences in maximal force-generating capability and cooperativity. Exchanging the mutant cTnT into isolated cardiac myofibrils also increased the free Ca 2؉ concentrations required for the activation of ATPase. In contrast, a deletion mutation ⌬E160 in cTnT that causes familial hypertrophic cardiomyopathy (HCM) decreased the free Ca 2؉ concentrations required for force generation, just as in the case of the other HCM-causing mutations in cTnT. The results indicate that cTnT mutations found in the two distinct forms of cardiomyopathy (i.e., HCM and DCM) change the Ca 2؉ sensitivity of cardiac muscle contraction in opposite directions. The present study strongly suggests that Ca 2؉ desensitization of force generation in sarcomere is a primary mechanism for the pathogenesis of DCM associated with the deletion mutation ⌬K210 in cTnT.C ontraction of the vertebrate-striated muscles (i.e., skeletal and cardiac muscles) is regulated by Ca 2ϩ through its binding to a specific regulatory protein complex, troponin (Tn), which is distributed at regular intervals along the entire thin filament (1, 2). Tn is a complex of three different proteins, troponin T (TnT; tropomyosin-binding component), troponin I (TnI; inhibitory component), and troponin C (TnC; Ca 2ϩ -binding component). On Ca 2ϩ binding to TnC, a Ca 2ϩ -induced interaction of TnC with TnI relieves the inhibitory action of TnI exerted on the thin filament and enables the myosin head to cyclically interact with actin in the thin filament and generate force. The Ca 2ϩ sensitivity of muscle contraction is determined by the Ca 2ϩ -binding affinity of TnC, which is dynamically altered through interaction with TnI and TnT in the myofilament lattice (3-8).Mutations in genes for cardiac troponin T (cTnT) and cardiac troponin I (cTnI) have been found to cause familial hypertrophic cardiomyopathy (HCM), an autosomal dominant heart disease characterized by asymmetrical ventricular hypertrophy with a high incidence of sudden death in young adults (9). We have already examined the effects of eight HCM-linked cTnT mutations (I79N, R92Q, ⌬E160, E244D, R278C, and two truncated mutants produced by a splice donor site mutation Int15G 1 3A) and six HCM-linked cTnI mutations (R145G, R145Q, R162W, ⌬K183, G203S, and K206Q) on the contractile functions of cardiac muscle by using a technique for exchanging the exogenous Tn complex into skinned muscle fibers and isolated myofibrils. We found t...

show abstract

“…All the CM hamsters share the genomic deletion of about 30-kb interval, which includes the two promoters and first exons of delta-sarcoglycan gene with consequent loss of its protein product [212,248,249]. The consequences of the genetic loss of delta-sarcoglycan in heart are related not only to sarcolemmal fragility but also to coronary vasospasm from disruption of dystrophin-associated protein complex [44].…”

Section: Syrian Cardiomyopathic Hamstermentioning

confidence: 99%

Rodent models of heart failure: an updated review

et al. 2012

View full text Add to dashboard Cite

Heart failure (HF) is one of the major health and economic burdens worldwide, and its prevalence is continuously increasing. The study of HF requires reliable animal models to study the chronic changes and pharmacologic interventions in myocardial structure and function and to follow its progression toward HF. Indeed, during the past 40 years, basic and translational scientists have used small animal models to understand the pathophysiology of HF and find more efficient ways of preventing and managing patients suffering from congestive HF (CHF). Each species and each animal model has advantages and disadvantages, and the choice of one model over another should take them into account for a good experimental design. The aim of this review is to describe and highlight the advantages and drawbacks of some commonly used HF rodents models, including both non-genetically and genetically engineered models, with a specific subchapter concerning diastolic HF models.

show abstract

Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, δ-sarcoglycan, in hamster: An animal model of disrupted dystrophin-associated glycoprotein complex

Cited by 281 publications

References 27 publications

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Ca ²⁺ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

Rodent models of heart failure: an updated review

Contact Info

Product

Resources

About

Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, δ-sarcoglycan, in hamster: An animal model of disrupted dystrophin-associated glycoprotein complex

Cited by 281 publications

References 27 publications

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Ca 2+ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

Rodent models of heart failure: an updated review

Contact Info

Product

Resources

About

Ca ²⁺ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy