Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart

Razeghi, Peter; Buksińska−Lisik, Małgorzata; Palanichamy, Nanthini; Stepkowski, Stanislaw M.; Frazier, O.H.; Taegtmeyer, Heinrich

doi:10.1096/fj.06-5718com

Cited by 19 publications

(9 citation statements)

References 20 publications

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“…Because Akt is not activated in the heterotopically transplanted rat heart, mTOR must be activated by Akt independent pathways in this model of cardiac atrophy 41 . Also consistent with the increase in protein synthesis in the unloaded rat heart is the increase of transcriptional regulators of ribosomal biogenesis and the activation of a hypertrophic gene program 43 . We have therefore proposed, that atrophic remodeling of the unloaded heart activates both protein synthesis and degradation 44 .…”

Section: Protein Turnover In Cardiac Atrophymentioning

confidence: 74%

Hypertrophy and Atrophy of the Heart

Razeghi¹,

Taegtmeyer²

2006

Annals of the New York Academy of Sciences

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The size of a cardiomyocyte is determined by relative rates of protein synthesis and degradation. Signaling pathways regulating myocardial protein synthesis have been extensively investigated, not the least because in patients hypertrophy increases cardiovascular morbidity and mortality. Until now strategies to reverse hypertrophy have relied on the inhibition of prohypertrophic signaling pathways. Here we review signaling pathways of atrophy in the heart and we present evidence in support of the idea that activating proatrophic signaling pathways in the presence of prohypertrophic signaling may be an attractive strategy to reverse hypertrophy.

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Section: Protein Turnover In Cardiac Atrophymentioning

confidence: 74%

Hypertrophy and Atrophy of the Heart

Razeghi¹,

Taegtmeyer²

2006

Annals of the New York Academy of Sciences

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“…It is possible these genes alter cardiac protein synthesis via rRNA processing. Although no definitive link between rRNA processing and heart development has been reported, increased MYC and rRNA have been shown in human hearts after mechanical unloading [82]. The enrichment of genes related to rRNA processing in candidate CNVs warrants further investigation.…”

Section: Resultsmentioning

confidence: 99%

Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways

et al. 2016

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Ebstein anomaly (EA) is a rare heart defect in which the tricuspid valve is malformed and displaced. The tricuspid valve abnormalities can lead to backflow of blood from the right ventricle to the right atrium, preventing proper circulation of blood to the lungs. Although the etiology of EA is largely unresolved, increased prevalence of EA in those with a family history of congenital heart disease suggests EA has a genetic component. Copy number variants (CNVs) are a major source of genetic variation and have been implicated in a range of congenital heart defect phenotypes. We performed a systematic, genome-wide search for CNVs in 47 isolated EA cases using genotyping microarrays. In addition, we used a custom HaloPlex panel to sequence three known EA genes and 47 candidate EA genes. We identified 35 candidate CNVs in 24 (51%) EA cases. Rare sequence variants in genes associated with cardiomyopathy were identified in 11 (23%) EA cases. Two CNVs near the transcriptional repressor HEY1, a member of the NOTCH signaling pathway, were identified in three unrelated cases. All other candidate CNVs were each identified in a single case. At least 11 of 35 candidate CNVs include genes involved in myocardial development or function, including multiple genes in the BMP signaling pathway. We identified enrichment of gene sets involved in histone modification and cardiomyocyte differentiation, supporting the involvement of the developing myocardium in the etiology of EA. Gene set enrichment analysis also identified ribosomal RNA processing, a potentially novel pathway of altered cardiac development in EA. Our results suggest an altered myocardial program may contribute to abnormal tricuspid valve development in EA. Future studies should investigate abnormal differentiation of cardiomyocytes as a potential etiological factor in EA.

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“…About 80–85% of the cellular RNA is ribosomal, and in human and rat heart muscle it has been shown that the rRNA content reflects the number of ribosomes (Millward et al 1973; Razeghi et al 2006). Assuming that the stability of mRNA, ribosomes and polysomes are similar in high and low oxidative fibers, the higher total RNA content in the rat high oxidative soleus muscle compared to the low oxidative EDL (Fig.…”

Section: Fiber Type-related Differences In the Machinery For Protein mentioning

confidence: 99%

The muscle fiber type–fiber size paradox: hypertrophy or oxidative metabolism?

et al. 2010

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An inverse relationship exists between striated muscle fiber size and its oxidative capacity. This relationship implies that muscle fibers, which are triggered to simultaneously increase their mass/strength (hypertrophy) and fatigue resistance (oxidative capacity), increase these properties (strength or fatigue resistance) to a lesser extent compared to fibers increasing either of these alone. Muscle fiber size and oxidative capacity are determined by the balance between myofibrillar protein synthesis, mitochondrial biosynthesis and degradation. New experimental data and an inventory of critical stimuli and state of activation of the signaling pathways involved in regulating contractile and metabolic protein turnover reveal: (1) higher capacity for protein synthesis in high compared to low oxidative fibers; (2) competition between signaling pathways for synthesis of myofibrillar proteins and proteins associated with oxidative metabolism; i.e., increased mitochondrial biogenesis via AMP-activated protein kinase attenuates the rate of protein synthesis; (3) relatively higher expression levels of E3-ligases and proteasome-mediated protein degradation in high oxidative fibers. These observations could explain the fiber type–fiber size paradox that despite the high capacity for protein synthesis in high oxidative fibers, these fibers remain relatively small. However, it remains challenging to understand the mechanisms by which contractile activity, mechanical loading, cellular energy status and cellular oxygen tension affect regulation of fiber size. Therefore, one needs to know the relative contribution of the signaling pathways to protein turnover in high and low oxidative fibers. The outcome and ideas presented are relevant to optimizing treatment and training in the fields of sports, cardiology, oncology, pulmonology and rehabilitation medicine.Electronic supplementary materialThe online version of this article (doi:10.1007/s00421-010-1545-0) contains supplementary material, which is available to authorized users.

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Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart

Cited by 19 publications

References 20 publications

Hypertrophy and Atrophy of the Heart

Hypertrophy and Atrophy of the Heart

Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways

The muscle fiber type–fiber size paradox: hypertrophy or oxidative metabolism?

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