Alterations in sarcomere function modify the hyperplastic to hypertrophic transition phase of mammalian cardiomyocyte development

Nixon, Benjamin R.; Williams, Alexandra F.; Glennon, Michael S; Feria, Alejandro E. de; Sebag, Sara C.; Baldwin, H. Scott; Becker, Jason R

doi:10.1172/jci.insight.90656

Cited by 9 publications

(13 citation statements)

References 55 publications

(63 reference statements)

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“…has recently been shown to be increased in angiotensin II-induced cardiac hypertrophy (Zhou et al, 2017), suggesting the pathophysiological role of cardiac formins in the development of cardiac hypertrophy. By contrast, we were not able to detect any upregulation of Fhod1 in heart tissues from Mybpc3-null mice, a model for cardiomyopathy (Harris et al, 2002;McConnell et al, 1999;Nixon et al, 2017). Although it is still possible that Fhod1 is upregulated in other types of pathological conditions and contributes to the pathogenesis via regulating actin organization in the sarcomere, the role of Fhod1 in the normal heart seems to be of minor relevance in the cardiac function.…”

Section: Discussioncontrasting

confidence: 68%

“…To estimate the effect of Fhod1 deletion on stress signaling in the heart, we performed quantitative real‐time PCR analysis of cardiac remodeling‐associated fetal genes that encode atrial natriuretic factor (ANF), B‐type natriuretic peptide (BNP), and β‐myosin heavy chain (β‐MHC; Figure d). Cardiac mRNA expression of these three genes in Fhod1 ‐null mice were comparable to that in control mice, whereas a significant increase was observed in Mybpc3 ‐null mice, which display a phenotype of cardiomyopathy (Harris et al, ; Matsuyama et al, ; Nixon et al, ). We further examined the effect of Fhod1 deletion on cardiac function by echocardiography, and found that there is no difference between Fhod1 ‐null and control mice (Table ).…”

Section: Resultsmentioning

confidence: 93%

“…As shown in Figure 6, Fhod1 protein expression was not induced in Mybpc3-null mice, a mouse model for cardiomyopathy (Harris et al, 2002;McConnell et al, 1999;Nixon et al, 2017). Thus, Fhod1 appears…”

Section: Fhod1 Expression In the Cardiomyopathic Heartmentioning

confidence: 83%

“…As shown in Figure 3d). Cardiac mRNA expression of these three genes in Fhod1-null mice were comparable to that in control mice, whereas a significant increase was observed in Mybpc3-null mice, which display a phenotype of cardiomyopathy (Harris et al, 2002;Matsuyama et al, 2018;Nixon et al, 2017). We further examined the effect of Fhod1 deletion on cardiac function by echocardiography, and found that there is no difference between Fhod1-null and control mice (Table 1).…”

Section: Effect Of Fhod1 Gene Disruption On the Heartmentioning

confidence: 95%

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Fhod1, an actin‐organizing formin family protein, is dispensable for cardiac development and function in mice

et al. 2019

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The formin family proteins have the ability to regulate actin filament assembly, thereby functioning in diverse cytoskeletal processes. Fhod3, a cardiac member of the family, plays a crucial role in development and functional maintenance of the heart. Although Fhod1, a protein closely‐related to Fhod3, has been reported to be expressed in cardiomyocytes, the role of Fhod1 in the heart has still remained elusive. To know the physiological role of Fhod1 in the heart, we disrupted the Fhod1 gene in mice by replacement of exon 1 with a lacZ reporter gene. Histological lacZ staining unexpectedly revealed no detectable expression of Fhod1 in the heart, in contrast to intensive staining in the lung, a Fhod1‐containing organ. Consistent with this, expression level of the Fhod1 protein in the heart was below the lower limit of detection of the present immunoblot analysis with three independent anti‐Fhod1 antibodies. Homozygous Fhod1‐null mice did not show any defects in gross and histological appearance of the heart or upregulate fetal cardiac genes that are induced under stress conditions. Furthermore, Fhod1 ablation did not elicit compensatory increase in expression of other formins. Thus, Fhod1 appears to be dispensable for normal development and function of the mouse heart, even if a marginal amount of Fhod1 is expressed in the heart.

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Section: Discussioncontrasting

confidence: 68%

Section: Resultsmentioning

confidence: 93%

Section: Fhod1 Expression In the Cardiomyopathic Heartmentioning

confidence: 83%

Section: Effect Of Fhod1 Gene Disruption On the Heartmentioning

confidence: 95%

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Fhod1, an actin‐organizing formin family protein, is dispensable for cardiac development and function in mice

et al. 2019

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“…Inhibition of myosin‐binding protein C (Mybpc3), a structural protein of the sarcomere that regulates myofilament stiffness and rigidity , reduces sarcomere density , leading to cardiac hypertrophy. Of interest, in heterozygous Mybpc3 +/− mice, the hypertrophic phenotype is mainly due to increase in CM cell size, however in homozygous Mybpc3 −/− animals this occurs mainly due to increased CM proliferation . The cardiac cytoskeleton in homozygous Mybpc3 knockout hearts contains less rigid sarcomeres and has decreased myofibrillar density.…”

Section: Remodelling Of the Sarcomeric Cytoskeleton During Cardiomyocmentioning

confidence: 99%

Cardiac regeneration and remodelling of the cardiomyocyte cytoarchitecture

2019

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Adult mammals are unable to regenerate their hearts after cardiac injury, largely due to the incapacity of cardiomyocytes (CMs) to undergo cell division. However, mammalian embryonic and fetal CMs, similar to CMs from fish and amphibians during their entire life, exhibit robust replicative activity, which stops abruptly after birth and never significantly resumes. Converging evidence indicates that formation of the highly ordered and stable cytoarchitecture of mammalian mature CMs is coupled with loss of their proliferative potential. Here, we review the available information on the role of the cardiac cytoskeleton and sarcomere in the regulation of CM proliferation. The actin cytoskeleton, the intercalated disc, the microtubular network and the dystrophin-glycoprotein complex each sense mechanical cues from the surrounding environment. Furthermore, they participate in the regulation of CM proliferation by impinging on the yes-associated protein/transcriptional co-activator with PDZ-binding motif, b-catenin and myocardin-related transcription factor transcriptional co-activators. Mastering the molecular mechanisms regulating CM proliferation would permit the development of innovative strategies to stimulate cardiac regeneration in adult individuals, a hitherto unachieved yet fundamental therapeutic goal.

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