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MCAT

Unit 2: Lesson 3

Foundation 3: Organ Systems

Blood oxygen levels may determine cardiac muscle regeneration

Problem

Whereas adult cardiomyocytes are unable to regenerate after cardiac failure, mammalian neonates have significant cardiomyocyte regeneration following injury. After birth, cardiomyocytes lose their regeneration capability around postnatal day 7, when they undergo cell-cycle arrest and mixing of blood ceases.
Researchers trying to determine the causes of this cell-cycle arrest noted that, in mice, there is an increase in mitochondrial DNA activity shortly after birth, indicating a switch from the anaerobic glycolysis metabolic pathway to the oxygen-dependent, mitochondrial oxidative phosphorylation (MOP) metabolic pathway. However, as the mice switched to MOP, researchers noted an increase in reactive oxygen species (ROS). The researchers then designed three additional experiments to further investigate the interaction between oxygen conditions, ROS, and cardiomyocyte growth and division.
Experiment 1
To directly test whether aerial oxygen can induce postnatal cardiomyocyte cell cycle arrest, neonatal mice were exposed to a hyperoxic or mildly hypoxic environment. Wheat germ agglutinin (WGA) staining and cell size quantification revealed significant decrease in cardiomyocyte cell size after hypoxia treatment, although hyperoxic treatment did not change the cell size. The presence of phosphorylated histone H3 Ser 10, a marker of G2-M progression, was significantly decreased in cardiomyocytes after hyperoxia treatment, and in contrast increased after hypoxia treatment. In addition, localization of kinase Aurora B at the cleavage furrow, a marker for cytokinesis, was decreased in hyperoxic hearts and mildly increased in hypoxic hearts.
Experiment 2
Mice were injected with Diquat, a chemical whose effect is to increase the number of ROS, and cardiomyocyte cytokinesis rate and cell size were again assessed according to Aurora B localization and WGA staining, respectively. Results are shown in Figure 1.
Figure 1 Effect of diquat injection on cardiomyocytes (A) cytokinesis rate, as determined by co-immunostaining with anti-Aurora B+, and (B) cell size, as determined by WGA staining. * and ** indicate statistically significant differences at p < 0.05 and p < 0.01, respectively.
Experiment 3
Mice were injected with N-acetyl-cysteine (NAC), a scavenger molecule that binds and neutralizes ROS, and cardiomyocyte cytokinesis rate and cell size were again assessed. Results are shown in Figure 2.
Figure 2 Effects of N-acetyl-cysteine (NAC) injection into cardiomyocytes on (A) cytokinesis rate, as determined by co-immunostaining with anti-Aurora B+, and (B) cell size, as determined by WGA staining. * and ** indicate statistically significant differences at p < 0.05 and p < 0.01, respectively.
Adapted from: Puente, B. N. et al. (2014). The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell, 157(3), 565–579.
How do cytokinesis or apoptosis rates relate to cardiomyocyte cell arrest?
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