Myoglobin Expression: Early Induction and Subsequent Modulation of Myoglobin and Myoglobin mRNA During Myogenesis

Weller, P A; Price, Melanie; Isenberg, Harvey; Edwards, Yvonne H.; Jeffreys, Alec J.

doi:10.1128/mcb.6.12.4539-4547.1986

Cited by 20 publications

(2 citation statements)

References 51 publications

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“…Traditionally, transcriptional levels have been considered a dominant (although not sole) determinant of protein levels [17,42,43]. We therefore hypothesized that Cetacean myoglobin genes would be highly active transcriptionally, and that study of their transcriptional mechanisms may provide insights into myoglobin transcriptional control, and regulatory evolution.…”

Section: Discussion Transcription Driven By Cetacean 5' Flanking Regi...mentioning

confidence: 98%

Comparative analysis of myoglobin in Cetaceans and humans reveals novel regulatory elements and evolutionary flexibility

Sackerson

Garcia

Medina

et al. 2023

Preprint

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Cetacea and other diving mammals have undergone numerous adaptations to their aquatic environment, among them high levels of the oxygen-carrying intracellular hemoprotein myoglobin in skeletal muscles, especially those responsible for swimming. Hypotheses regarding the mechanisms leading to these high myoglobin levels often invoke exercise, hypoxia, and other physiological pathways that impact gene regulation, and increase myoglobin gene expression. Here we explore an alternative hypothesis: that Cetacean myoglobin genes have evolved high levels of transcription driven by the intrinsic developmental mechanisms that drive muscle cell differentiation. We have used luciferase assays in differentiated C2C12 cells to test this hypothesis. Contrary to our hypothesis, we find that the myoglobin gene from the minke whale,Balaenoptera acutorostrata, has a low level of expression, less than 10% that of humans. This low expression level is broadly shared among Cetaceans, and Artiodactylans. Previous work on regulation of the human gene has identified a core muscle-specific enhancer comprised of two regions, the “AT element” and a C-rich sequence 5’ of the AT element termed the “CCAC-box”. Comparative analysis of the minke whale gene supports the importance of the AT element, but the minke whale CCAC-box ortholog has little effect. Instead, critical positive input has been identified in a G-rich region 3’ of the AT element. Also, a conserved E-box in exon 1 positively affects expression, despite having been assigned a repressive role in the human gene. Last, a novel region 5’ of the core enhancer has been identified, which we hypothesize may function as a boundary element. These results illustrate regulatory flexibility during evolution. They also support the hypothesis that the induction of transcription by physiological signaling pathways, and evolved protein stability are important in leading to the high myoglobin protein levels found in Cetaceans.

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Section: Discussion Transcription Driven By Cetacean 5' Flanking Regi...mentioning

confidence: 98%

Comparative analysis of myoglobin in Cetaceans and humans reveals novel regulatory elements and evolutionary flexibility

Sackerson

Garcia

Medina

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Cetaceans are notable for the high levels of the oxygen carrying protein myoglobin in their skeletal muscle, and hence myoglobin concentration correlates strongly with diving capability [ 25 , 42 ]. Traditionally, transcriptional levels have been considered a dominant, although not sole, determinant of protein levels [ 43 – 45 ]. We therefore hypothesized that cetacean myoglobin genes would be highly active transcriptionally, and that comparison of their transcriptional mechanisms with that of humans [reviewed in 17 ] may provide insights into myoglobin transcriptional control and regulatory evolution.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of the myoglobin gene in whales and humans reveals evolutionary changes in regulatory elements and expression levels

Sackerson,

Garcia,

Medina

et al. 2023

PLoS ONE

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Cetacea and other diving mammals have undergone numerous adaptations to their aquatic environment, among them high levels of the oxygen-carrying intracellular hemoprotein myoglobin in skeletal muscles. Hypotheses regarding the mechanisms leading to these high myoglobin levels often invoke the induction of gene expression by exercise, hypoxia, and other physiological gene regulatory pathways. Here we explore an alternative hypothesis: that cetacean myoglobin genes have evolved high levels of transcription driven by the intrinsic developmental mechanisms that drive muscle cell differentiation. We have used luciferase assays in differentiated C2C12 cells to test this hypothesis. Contrary to our hypothesis, we find that the myoglobin gene from the minke whale, Balaenoptera acutorostrata, shows a low level of expression, only about 8% that of humans. This low expression level is broadly shared among cetaceans and artiodactylans. Previous work on regulation of the human gene has identified a core muscle-specific enhancer comprised of two regions, the “AT element” and a C-rich sequence 5’ of the AT element termed the “CCAC-box”. Analysis of the minke whale gene supports the importance of the AT element, but the minke whale CCAC-box ortholog has little effect. Instead, critical positive input has been identified in a G-rich region 3’ of the AT element. Also, a conserved E-box in exon 1 positively affects expression, despite having been assigned a repressive role in the human gene. Last, a novel region 5’ of the core enhancer has been identified, which we hypothesize may function as a boundary element. These results illustrate regulatory flexibility during evolution. We discuss the possibility that low transcription levels are actually beneficial, and that evolution of the myoglobin protein toward enhanced stability is a critical factor in the accumulation of high myoglobin levels in adult cetacean muscle tissue.

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Species specificity of transferein binding, endocytosis and iron internalization by cultured chick myogenic cells

Sorokin

Morgan

1988

J Comp Physiol B

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The ability of unlabelled heterologous transferrin to interact with transferrin receptors on developing chick myogenic cells was investigated by measuring their capacity to inhibit the surface-binding and internalization of 125I- and 59Fe-labelled ovotransferrin. Transferrins from rat, rabbit, human, and a species of kangaroo (Macropus fuliginosus) were unable to inhibit either surface-binding or internalization of labelled ovotransferrin even at concentrations ten times the molar concentration of the ovotransferrin. Transferrins isolated from the serum of a toad (Bufo marinus) and a lizard (Teliqua rugosa), when added at high concentrations, were found to reduce surface-binding of 125I-Tf by 20-25% but did not inhibit internalization of either 125I-Tf or 59Fe. This suggests that the effects of toad and lizard transferrins are due to non-specific binding to the myogenic cells. In contrast, inhibition of both surface-binding and internalization of labelled ovotransferrin was found when myogenic cells were incubated in the presence of the homologous transferrin (ovotransferrin). The species-specificity of transferrin binding, endocytosis and iron internalization did not vary with the state of proliferation or differentiation of the myogenic cells. However, the intracellular iron utilization was found to differ between differentiating presumptive and terminally differentiated myotubes. Internalized 59Fe was fractioned by gel filtration. In dividing and non-dividing presumptive myoblasts 59Fe was found to elute in three peaks, two with elution volumes corresponding to ferritin and transferrin and one at greater elution volume than that of myoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)

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Myoglobin Expression: Early Induction and Subsequent Modulation of Myoglobin and Myoglobin mRNA During Myogenesis

Cited by 20 publications

References 51 publications

Comparative analysis of myoglobin in Cetaceans and humans reveals novel regulatory elements and evolutionary flexibility

Comparative analysis of myoglobin in Cetaceans and humans reveals novel regulatory elements and evolutionary flexibility

Comparative analysis of the myoglobin gene in whales and humans reveals evolutionary changes in regulatory elements and expression levels

Species specificity of transferein binding, endocytosis and iron internalization by cultured chick myogenic cells

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