InsuYcient blood supply during acute infarction and chronic ischemia leads to tissue hypoxia which can signiWcantly alter gene expression patterns in the heart. In contrast to most mammals, some teleost Wshes are able to adapt to extremely low oxygen levels. We describe here that chronic constant hypoxia (CCH) leads to a smaller ventricular outXow tract, reduced lacunae within the central ventricular cavity and around the trabeculae and an increase in the number of cardiac myocyte nuclei per area in the hearts of two teleost species, zebraWsh (Danio rerio) and cichlids (Haplochromis piceatus). In order to identify the molecular basis for the adaptations to CCH, we proWled the gene expression changes in the hearts of adult zebraWsh. We have analyzed over 15,000 diVerent transcripts and found 376 diVerentially regulated genes, of which 260 genes showed increased and 116 genes decreased expression levels. Two notch receptors (notch-2 and notch-3) as well as regulatory genes linked to cell proliferation were transcriptionally upregulated in hypoxic hearts. We observed a simultaneous increase in expression of IGF-2 and IGFbp1 and upregulation of several genes important for the protection against reactive oxygen species (ROS). We have identiWed here many novel genes involved in the response to CCH in the heart, which may have potential clinical implications in the future.
Fish may be extremely hypoxia resistant. We investigated how muscle fibre size and oxidative capacity in zebrafish (Danio rerio) adapt during severe chronic hypoxia. Zebrafish were kept for either 3 or 6 weeks under chronic constant hypoxia (CCH) (10% air/90%N2 saturated water). We analyzed cross-sectional area (CSA), succinate dehydrogenase (SDH) activity, capillarization, myonuclear density, myoglobin (Mb) concentration and Mb mRNA expression of high and low oxidative muscle fibres. After 3 weeks of CCH, CSA, SDH activity, Mb concentration, capillary and myonuclear density of both muscle fibre types were similar as under normoxia. In contrast, staining intensity for Mb mRNA of hypoxic high oxidative muscle fibres was 94% higher than that of normoxic controls (P<0.001). Between 3 and 6 weeks of CCH, CSA of high and low oxidative muscle fibres increased by 25 and 30%, respectively. This was similar to normoxic controls. Capillary and myonuclear density were not changed by CCH. However, in high oxidative muscle fibres of fish maintained under CCH, SDH activity, Mb concentration as well as Mb mRNA content were higher by 86%, 138% and 90%, respectively, than in muscle fibres of fish kept under normoxia (P<0.001). In low oxidative muscle fibres, SDH activity, Mb and Mb mRNA content were not significantly changed. Under normoxia, the calculated interstitial oxygen tension required to prevent anoxic cores in muscle fibres (PO2crit) of high oxidative muscle fibres was between 1.0 and 1.7 mmHg. These values were similar at 3 and 6 weeks CCH. We conclude that high oxidative skeletal muscle fibres of zebrafish continue to grow and increase oxidative capacity during CCH. Oxygen supply to mitochondria in these fibres may be facilitated by an increased Mb concentration, which is regulated by an increase in Mb mRNA content per myonucleus.
The globin family, including hemoglobin, myoglobin, neuroglobin and cytoglobin, plays an important role in oxygen storage and delivery. Myoglobin has been shown to be necessary for cardiac function during development, but no information is currently available on the developmental regulation of myoglobin gene expression during embryogenesis. In this study, we used whole mount in situ hybridization to visualize myoglobin mRNA expression during zebrafish development. Our results show for the first time the spatial and temporal gene expression pattern of myoglobin during embryogenesis. Myoglobin was expressed as a maternal RNA and ubiquitous expression was observed until the end of gastrulation. At later stages of development, we discovered novel expression domains for myoglobin, including several nonmuscular ones. Environmental stresses, like low oxygen tension (hypoxia) can lead to a developmental delay in zebrafish embryos. We show here that hypoxic stress induces myoglobin expression in skeletal muscle cells of anterior somites and in the dorsal aorta of zebrafish larvae. Finally, we analyzed the role of myoglobins in development by targeted gene knock-down. Silencing myoglobin in zebrafish embryos with gene-specific morpholinos led to a dose dependent curvature, vascular defects, enlarged pericardia and reduction of the gut. In conclusion, our results indicate that myoglobin plays a crucial role in zebrafish development and is important for angiogenesis and gut development.
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