Cardiomyocyte cell cycle arrest
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Cardiomyocyte cell cycle arrest
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[post_date] => 2024-12-23 17:59:25
[post_date_gmt] => 2024-12-23 22:59:25
[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
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.
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[question] => How do cytokinesis or apoptosis rates relate to cardiomyocyte cell cycle arrest?
[value] => Array
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[answer] => 1
[description] => Reason for Correct Answer:
Cytokinesis is the division of cytoplasm during cell division, whereas apoptosis is the process of programmed cell death.
When cells are arrested, they are not progressing through the cell cycle and, generally, cytokinesis does not occur.
Conversely, when cytokinesis occurs at high rates, there is a low level of cell cycle arrest.
Reason for Incorrect Answer:
B. Cell cycle arrest means cells are not actively replicating and dividing, which means mitosis and cytokinesis do not occur.
C. High cell turnover means that a lot of cells are dying and being replaced by younger cells. It is often used to describe skin cells, which are constantly “sloughing off” and being replaced by new cells underneath. It doesn’t really apply to cells like cardiomyocytes, which are “fixed” and continue to function for long periods of time. Further, a low apoptosis rate would not require cell turnover or replacement with other cells.
D. A high apoptosis rate would be associated with a high rate of cell turnover in cells that are able to proliferate and replace dying cells.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. A high cytokinesis rate correlates with low levels of cardiomyocyte cell cycle arrest.
)
[1] => Array
(
[each_answer] => B. An increase in cardiomyocyte cell cycle arrest corresponds with an increase in cytokinesis rate.
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[2] => Array
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[each_answer] => C. A low apoptosis rate correlates with a high rate of cardiomyocyte cell turnover.
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[each_answer] => D. A high apoptosis rate correlates with a low rate of cardiomyocyte cell turnover.
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => What conclusion is most supported by the results of Experiment 1?
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[answer] => 4
[description] => Reason for Correct Answer:
Experiment 1 assesses the effect of aerial oxygen (hypoxic/low oxygen conditions vs hyperoxic/high oxygen conditions) on three things: cell size, G2-M progression, and the cytokinesis.
Whereas cardiomyocyte cell size was decreased under hypoxic conditions, the results state that (1) G2-M progression and (2) the rate of cytokinesis (according to Aurora B localization) were both INCREASED under hypoxic conditions.
This supports the notion that oxygen levels do affect cardiomyocyte proliferation, with hypoxic conditions favoring cell cycle progression and inhibiting cell cycle arrest.
FYI: “Perinatal” refers to the period both during and after pregnancy, whereas “postnatal” refers to the period after birth, and “neonates” are young infants. The MCAT will not likely try to trip you up by listing such terminology incorrectly. Instead, focus on the main concepts of the passage for questions like this.
Experiment 1 assesses the effect of aerial oxygen (hypoxic/low oxygen conditions vs hyperoxic/high oxygen conditions) on three things: cell size, G2-M progression, and the cytokinesis.
Whereas cardiomyocyte cell size was decreased under hypoxic conditions, the results state that (1) G2-M progression and (2) the rate of cytokinesis (according to Aurora B localization) were both INCREASED under hypoxic conditions.
This supports the notion that oxygen levels do affect cardiomyocyte proliferation, with hypoxic conditions favoring cell cycle progression and inhibiting cell cycle arrest.
FYI: “Perinatal” refers to the period both during and after pregnancy, whereas “postnatal” refers to the period after birth, and “neonates” are young infants. The MCAT will not likely try to trip you up by listing such terminology incorrectly. Instead, focus on the main concepts of the passage for questions like this.
Reason for Incorrect Answer:
A. Though the results of Experiment 1 DO in fact suggest that hyperoxic conditions can induce cell cycle arrest, it is important to note that Experiment 1 does NOT examine or deal with reactive oxygen species (ROS). Therefore, no conclusions about the involvement of “oxidative and intracellular stress” can be drawn by Experiment 1.
B. Experiment 1 describes the effect of hyperoxia and hypoxia on cardiomyocyte cell division, growth, and cell cycle progression; it does NOT focus on the reverse influence of cell division on oxygenation. Further, it doesn’t make much sense that this cellular process would greatly influence blood oxygenation overall.
C. Experiment 1 actually states that hypoxic, NOT hyperoxic, conditions increased the rate of G2-M cell cycle progression and cytokinesis (Aurora B localization), thus suggesting that hypoxic conditions promote cell division.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. Exposure to aerial oxygen induces cardiomyocyte cell cycle arrest after birth due to oxidative and intracellular stress.
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[each_answer] => B. The rate of cardiomyocyte cell division at least in part helps determine the level of oxygenation perinatally and postnatally.
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[each_answer] => C. In neonates, cardiomyocytes begin to more actively grow and divide after birth, once blood oxygen levels increase.
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[each_answer] => D. Perinatal and postnatal oxygen concentration affects cardiomyocyte proliferation in neonates, with hypoxic conditions inhibiting cell cycle arrest.
)
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => Which condition(s) would prenatal or postnatal exposure to Diquat most likely pose an increased risk according to the passage?
I. Small cardiomyocyte size
II. Premature cell-cycle arrest
III. Excess cell proliferation
[value] => Array
(
[answer] => 2
[description] => Reason for Correct Answer:
The Experiment 1 description, as well as the figure for Figure 1, state that Aurora B is a marker for cytokinesis.
Figure 1A shows that Diquat decreases the # of Aurora B+ cardiomyocytes, which suggests that it decreases the rate of cytokinesis. And, Figure 1B it also shows that Diquat increases cell size.
If it decreases the rate of cytokinesis and cell division, this means that Diquat increases cell-cycle arrest. It follows that fetuses and neonates exposed to Diquat may run the risk of premature cell-cycle arrest (II).
Reason for Incorrect Answer:
A. Figure 1B shows that injection with Diquat INCREASED the size of mouse cardiomyocytes.
C. Figure 1A shows that Diquat decreases the # of Aurora B+ cardiomyocytes, which suggests that it decreases the rate of cytokinesis and therefore decreases cell proliferation.
D. Figure 1B shows that injection with Diquat INCREASED the size of mouse cardiomyocytes, so (I.) is incorrect.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. I only
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[each_answer] => B. II only
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[each_answer] => C. III only
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[each_answer] => D. I and III only
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[quiz_unique_key] => 1403770772
[question] => Which intervention might be an effective treatment for preventing cardiac abnormalities in premature infants?
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[answer] => 1
[description] => Reason for Correct Answer:
Up front, the passage states that cardiomyocytes “lose their regenerative capability” and undergo cell cycle arrest shortly after birth. This suggests that premature infants, born early, may be at risk for cardiac abnormalities caused by cardiomyocytes arresting before they have adequately proliferated. Hypothetically, it may therefore be effective to treat them with a medication that delays cell-cycle arrest and promotes proliferation in cardiomyocytes.
The rest of the passage makes it clear that reactive oxygen species (ROS) promote cell cycle arrest: Figure 1A shows that Diquat injection (which increases ROS) decreases cytokinesis and therefore increases cell cycle arrest, and Figure 2A shows that treatment with NAC (which decreases ROS) promotes cytokinesis and therefore cell proliferation.
A drug that similarly decreases oxidative stress and the formation of ROS could hypothetically prevent cell cycle arrest and increase cardiomyocyte proliferation in premature infants
Reason forIncorrect Answer:
B. The results of Experiment 2 and 3 suggest that reactive oxygen species promote cell cycle arrest, and increasing ROS would likely be harmful to the premature baby’s condition.
C. Experiment 1 states that hyperoxia increases cell cycle arrest, so treatment with hyperbaric oxygen would be harmful.
D. Experiment 3 states that NAC binds and eliminates ROS. So, eliminating NAC would increase ROS, which would be harmful to the premature baby.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. Drugs that promote reduction of mitochondrial-dependent oxidative stress
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[1] => Array
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[each_answer] => B. Drugs that mimic the effects of reactive oxygen species
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[each_answer] => C. Treatment with hyperbaric oxygen
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[each_answer] => D. Drugs that bind and eliminate N-acetyl-cysteine (NAC)
)
)
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[4] => Array
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[quiz_unique_key] => 1403770772
[question] => Following birth, cardiomyocytes would most likely exhibit:
[value] => Array
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[answer] => 3
[description] => Reason for Correct Answer:
According to the passage, cardiomyocytes undergo cell cycle arrest after birth.
Cyclin and cyclin-dependent kinases (CDKs) regulate progression through the cell cycle; generally, they PROMOTE progression through the cell cycle. Conversely, CDK inhibitors block cell cycle progression.
Accordingly, you could expect down-regulation of cyclins and cyclin-dependent kinases (and upregulation of cyclin-dependent kinase inhibitors) in cardiomyocytes that are undergoing cell cycle arrest following birth.
Reason for Incorrect Answer:
A. Paragraph 2 states that ROS increase following birth.
B. Tyrosine-dependent kinases are not tightly linked to cell cycle regulation, as are cyclins and CDKS.
D. The description of Experiment 1 states that H3 Ser 10 levels decrease under hyperoxic conditions, so they would also be expected to decrease with increased oxygen exposure following birth.
)
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[0] => Array
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[each_answer] => A. decreased levels of reactive oxygen species.
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[each_answer] => B. upregulation of tyrosine-dependent kinase inhibitors.
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[each_answer] => C. down-regulation or inhibition of cyclin-dependent kinases.
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[each_answer] => D. increased levels of phosphorylated histone H3 Ser 10.
)
)
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[5] => Array
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[quiz_unique_key] => 1325138223
[question] => Which function of Aurora B is most likely according to the passage?
[value] => Array
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[answer] => 4
[description] => Reason for Correct Answer:
The paragraph describing Experiment 1 states that Aurora B is a kinase, which means that its function is phosphorylation – or adding a phosphate group – to another protein.
The paragraph also states that its localization to the cleavage furrow is a marker for cytokinesis, which is the separation of two daughter cells corresponding to the end of mitosis.
This suggests that Aurora B is likely involved in the processes of mitosis and cytokinesis, which rely heavily on microtubule assembly (for the separation of daughter chromosomes and other functions) and actin and myosin assembly (for the formation of the contractile ring between daughter cells during cytokinesis).
Therefore, it is most reasonable to conclude that Aurora B may be involved in microtubule and/or microfilament assembly during these processes, or else some other process important for cell division.
Note: Cytokinesis generally occurs at the end of end of cytokinesis. The cleavage furrow and contractile ring are shown below.
Reason for Incorrect Answer:
A. Though Aurora B may be involved in microtubule assembly and other processes involved in mitosis and cytokinesis, the passage clearly states that Aurora B is a kinase, which means it phosphorylates other proteins. (See Experiment 1 description.)
B. Experiment 1 description states that Aurora B localization itself is a marker of cytokinesis. Figure 1 and 2 further state that the cells were assayed for Aurora B using immunostaining with anti-Aurora B (anitbody). This suggests that the assay is identifying Aurora B directly, NOT detecting a protein target after its phosphorylation by Aurora B.
C. The passage clearly states that Auroba B is a kinase, which means it phosphorylates other proteins. (See Experiment 1 description). And, it doesn’t mention any involvement with ROS.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. De-phosphorylation of microtubule-associated proteins, which helps ensure proper separation of chromosomes
)
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[each_answer] => B. Phosphorylation of a protein target that can in turn be detected by immunostain in experiments assaying the rate of cytokinesis
)
[2] => Array
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[each_answer] => C. De-phosphorylation of an enzyme involved in the breakdown of ROS
)
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[each_answer] => D. Phosphorylation of proteins involved in microtubule and myosin II assembly and disassembly
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Figure 1
Figure 2 
