Altered regional cardiac wall mechanics are associated with differential cardiomyocyte calcium handling due to nebulette mutations in preclinical inherited dilated cardiomyopathy

Maiellaro-Rafferty, Kathryn; Wansapura, Janaka; Mendsaikhan, Uzmee; Osińska, Hanna; James, Jeanne; Taylor, Michael D.; Robbins, Jeffrey; Kranias, Evangelia G.; Towbin, Jeffrey A.; Purevjav, Enkhsaikhan

doi:10.1016/j.yjmcc.2013.04.021

Cited by 31 publications

(35 citation statements)

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“…The sarcomere length (distance between two thick myosin filaments) was measured on sections from each group of young adult or old, WT, or Berkeley sickle mice, for a total of 1,295 sarcomeres. Lengths of sarcomeres were determined using ImageJ (NIH, Public Domain) and subsequently converted to micrometers (91,92).…”

Section: Methodsmentioning

confidence: 99%

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Bakeer

James

Roy

et al. 2016

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

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Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.sickle cell anemia | cardiomyopathy | restrictive physiology | arrhythmias | sudden death S ickle cell anemia (SCA) results from a point mutation in the β-globin gene and affects millions world-wide. It is characterized by production of the mutant hemoglobin S (HbS), which polymerizes upon deoxygenation and distorts the shape of RBCs, increasing their propensity to hemolysis and microvascular occlusion. Recurrent cycles of HbS polymerization result in a host of acute and chronic complications, including vaso-occlusive pain crisis, chronic hemolytic anemia, and organ damage. SCA-associated mortality rates have improved because of early diagnosis with universal newborn screening, immunization, and penicillin prophylaxis, which has changed the natural history of SCA (1, 2) and the impact of SCA on organ pathologies is now becoming evident.Despite improved early survival, nearly one-third of young adults with SCA die suddenly (3-9). The sickle myocardium has been presumed to be relatively resistant to the effects of sickling (10), and studies/autopsies show little evidence of atherosclerosis or coronary disease (11)(12)(13)(14). Mildly increased systolic pulmonary arterial pressure (PAP) estimated by tricuspid regurgitant jet vel...

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Section: Methodsmentioning

confidence: 99%

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Bakeer

James

Roy

et al. 2016

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

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“…associated protein, nebulette (Table 1). Nebulette encodes a sarcomeric Z-disk protein that contributes to muscle force generation via its interaction with actin and cardiac tropomyosintroponin complex, and participating in force transmission of the cardiac myofibril via the Z-disk assembly (47). Transgenic mice with cardiomyocyte-restricted expression of human mutant nebulette develop dilated cardiomyopathy at 6 months of age (48).…”

Section: D-dige Spotmentioning

confidence: 99%

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

Das

Durrant

Koka

et al. 2014

Journal of Biological Chemistry

142

122

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Background: Elevated mammalian target of rapamycin (mTOR) signaling contributes to diabetic complications. Results: mTOR inhibitor, rapamycin, improves metabolic status and cardiac function, attenuates oxidative stress, and alters antioxidant and contractile protein expression in type 2 diabetic mice. Conclusion: Rapamycin may provide metabolic and cardiac benefits in diabetic mice. Significance: mTOR inhibition may be an attractive novel therapeutic strategy for diabetes-related complications.

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“…85 myocytes from the same mice showed an increased baseline calcium decay rate in the G202R transgenic mice, suggesting reduced myofilament calcium sensitivity, whereas cardiomyocytes from A592E transgenic mice were shorter and exhibited blunted calcium decay in response to isoproterenol-mediated stress. 65 Ultrastructural analyses of G202R transgenic hearts compared with controls showed increased sarcomere length and I-band width, enlarged t-tubules as well as desmosomal separation at the intercalated disc. 65 Similar intercalated disc abnormalities, although not as severe, were observed in hearts from A592E transgenic mice.…”

Section: N-rap (Nebulin-related Anchoring Protein)mentioning

confidence: 97%

“…65 Ultrastructural analyses of G202R transgenic hearts compared with controls showed increased sarcomere length and I-band width, enlarged t-tubules as well as desmosomal separation at the intercalated disc. 65 Similar intercalated disc abnormalities, although not as severe, were observed in hearts from A592E transgenic mice. At the molecular level, downregulation and disruption of troponin I, cardiac troponin T, and tropomyosin as well as cleavage of filamin C and myopalladin were found in the hearts of 6-month-old G202R transgenic mice compared with control mice.…”

Section: N-rap (Nebulin-related Anchoring Protein)mentioning

confidence: 97%

“…64 Cardiac magnetic resonance imaging at 3 months of age before the onset of the DCM phenotype showed geometric remodeling and reduced torsion in G202R transgenic mice, while A592E transgenic mice exhibited enhanced twist and untwisting rate. 65 Furthermore, ex vivo experiments on isolated adult cardioskeleton; 54,56 (3) the Zis1 and PEVK regions of titin, a giant protein stretching half a sarcomere from the Z-line to the M-line; 33,55,57 (4) zyxin, associated with focal adhesions and actin based structures, involved in cytoskeletal organization; 22 (5) neuronal Wiscott-Aldrich syndrome protein (N-WASP/ WASL), regulating actin polymerization; 53 and (6) the Xin actin-binding repeat-containing (XIRP) family members Xin and XIRP2 with which they interact transiently during development and remodeling. 58 Furthermore, both the SH3 domain and the nebulin repeats bind with high affinity to α-actinin in the Z-line.…”

Section: Nebulettementioning

confidence: 99%

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Roles of Nebulin Family Members in the Heart

Bang

Chen

2015

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp ment. 4,10,11,13-15 N-RAP is the second largest member of the nebulin family (193)(194)(195)(196) kDa in humans) containing 46 nebulin repeats of which 35 are organized into 5 super repeats, 16,17 while nebulette (109 kDa), 3,18 LASP-1 (37 kDa), 19,20 and LASP-2 (34 kDa) 21-23 contain only simple nebulin repeats. Nebulette contains up to 23 repeats, 3 while LASP-1 and LASP-2 contain only 2 and 3 repeats, respectively. Except for N-RAP the family members also share an SH3 domain at their C-terminus, and N-RAP, LASP-1, and LASP-2 contain an N-terminal LIM domain not present in nebulin or nebulette. Apart from their similar domain structure and linkage to actin, the members of the nebulin family are quite heterogeneous both with respect to molecular size (34-900 kDa) and expression pattern as well as function, which includes roles in stabilization and scaffolding of cytoskeletal structures, cell migration, and organization of the actin cytoskeleton. In the present review, we will focus on the roles of nebulin family members in the heart. NebulinMutations in the nebulin gene are causative for nemaline myopathy 24,25 and the function of nebulin in skeletal muscle has been extensively studied both in vitro and in vivo, revealing its multifunctional role in various processes required for efficient myofibrillar force generation, including (1) regulation he nebulin family of actin-binding cytoskeletal proteins comprises nebulin, nebulette, N-RAP (Nebulinrelated anchoring protein), LASP-1 (LIM and Src homology 3 (SH3) Protein-1), and LASP-2 (LIM and SH3 Protein-2/LIM-Nebulette), a splice variant of nebulette. 1 The members of the family contain various numbers of 35-residue nebulin repeats, containing a central conserved SDXXYK consensus motif 2,3 and named after the founding member nebulin, which includes up to 185 copies of the repeat (Figure). 4,5 Nebulin is the largest member of the nebulin family, with a molecular weight ranging from 600 to 900 kDa and expressed predominantly in skeletal muscle, where it stretches along the actin thin filament with its C-terminal region anchored in the sarcomeric Z-line and its N-terminal region extending towards the pointed end of the thin filament. 4,6 For reviews on the sarcomere and the Z-line, see Frank et al 7 and Sheikh et al. 8 Within the central part of nebulin (repeats 9-162), the nebulin repeats are organized into "super repeats" of 7 repeats, containing a conserved WLKGIGW motif at the end of the third repeat of each super repeat. 4 Each nebulin repeat binds to an actin monomer, 9-12 while the nebulin super repeats correspond to the architecture of the thin filament with 1 tropomyosin/ troponin complex for every 7 actin subunits, and interact with troponin T and tropomyosin along the length of the thin fila- Roles of Nebulin Family Members in the HeartMarie-Louise Bang, PhD; Ju Chen, PhDThe members of the nebulin protein family, including nebulin, nebulette, LASP-1, LASP-2, ...

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Altered regional cardiac wall mechanics are associated with differential cardiomyocyte calcium handling due to nebulette mutations in preclinical inherited dilated cardiomyopathy

Cited by 31 publications

References 30 publications

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

Roles of Nebulin Family Members in the Heart

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