Dietary supplements and the mTOR pathway
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- Dietary supplements and the mTOR pathway
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Dietary supplements and the mTOR pathway
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[ID] => 553655
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[post_date] => 2024-08-06 12:38:14
[post_date_gmt] => 2024-08-06 16:38:14
[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.
Dietary branched-chain amino acids (BCAAs) are marketed to athletes as supplements that stimulate protein formation in muscle and reduce muscle breakdown. BCAAs are amino acids that have a side chain consisting of an aliphatic group with a branch point; they include leucine, isoleucine, and valine (Figure 1). BCAAs account for 35% of the essential amino acids found in muscle proteins.
Table 1 Branched-chain amino acid (BCAA) properties
The mammalian target of rapamycin (mTOR) is a conserved serine/threonine protein kinase that regulates protein metabolism. mTOR integrates intracellular inputs, such as BCAAs and growth factors, to promote protein translation. The activation of mTOR results in the phosphorylation of a translation initiation protein called eIF4EBP1. Unphosphorylated eIF4EBP1 blocks translation by sequestering a different translation initiation protein called eIF4E. eIF4E is responsible for binding the mRNA cap and bringing the mRNA transcript to the ribosome. Phosphorylation of eIF4EBP1 by mTOR causes eIF4EBP1 to release eIF4E, resulting in the initiation of translation.
Recently, studies in animal models have suggested that certain BCAAs are more effective than others in activating mTOR (Figure 1); this suggests that nutritional supplements could be more effectively targeted toward building muscle through this pathway. Figure 1 shows the percentage of phosphorylated eIF4EBP1 in two mice at baseline (control) and following supplementation with each of the three BCAAs investigated here.
Figure 1 Percentage of phosphorylated eIF4EBP1 following supplementation; error bars represent standard error
[post_title] => Dietary supplements and the mTOR pathway
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[post_name] => dietary-supplements-mtor-pathway
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[post_modified] => 2024-12-23 06:28:27
[post_modified_gmt] => 2024-12-23 11:28:27
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[quiz_unique_key] => 602779517
[question] => What is the approximate pI of the branched-chain amino acids?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
The pI, or isoelectric point, is the pH at which an amino acid carries no net electrical charge.
A functional group exists in protonated form at any pH below its pKa and in deprotonated form at any pH above its pKa.
The pI of an amino acid with an uncharged R group is the average of the pKas of the carboxyl and amino groups. At this pH, the amino acid exists as a zwitterion and has no net charge.
According to the table, the average of the pKas of the carboxyl and amino groups is around (9.7 + 2.3) / 2 = 6.0.
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[answers] => Array
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[0] => Array
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[each_answer] => A. 2.3
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[each_answer] => B. 6.0
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[2] => Array
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[each_answer] => C. 9.7
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[3] => Array
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[each_answer] => D. This cannot be determined without additional data.
)
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[1] => Array
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[quiz_unique_key] => 3243476205
[question] => Which of the following amino acid substitutions would be least likely to disrupt protein functionality?
[value] => Array
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[answer] => 3
[description] => Reason for Correct Answer:
A protein can be functional only if it is folded into its proper conformation (three-dimensional structure), which depends on the properties of the individual amino acids.
Amino acid substitutions are least disruptive to protein structure when the R group maintains the previous amino acid’s charge and polar/nonpolar properties. Less critical, but sometimes still important, are changes in the size or shape of the side chains.
Isoleucine to lysine, and leucine to arginine, are mutations that both involve the conversion of an uncharged, nonpolar amino acid to a charged amino acid.
Though both glutamic acid and glutamine are polar, this conversion results in a loss of a negative charge, which may be important for side-chain interactions.
Both valine and alanine are uncharged and nonpolar, therefore this substitution would be the least disruptive to the protein’s three-dimensional structure, and in turn, its functionality.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Glutamic acid → glutamine
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[each_answer] => B. Isoleucine → lysine
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[2] => Array
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[each_answer] => C. Valine → alanine
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[each_answer] => D. Leucine → arginine
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[2] => Array
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[quiz_unique_key] => 2187790141
[question] => In Figure 1, which mouse has a higher level of mTOR basal activity?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
In Figure 1, mTOR activity is measured by the phosphorylation levels of eIF4EBP1.
In Figure 1, the basal activity of mTOR is measured by the baseline levels of eIF4EBP1 phosphorylation.
The baseline levels of eIF4EBP1 phosphorylation are measured by the control sample.
Mouse 2 has higher levels of eIF4EBP1 phosphorylation and therefore the highest basal mTOR activity.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Mouse 1
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[each_answer] => B. Mouse 2
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[each_answer] => C. Both mice have the same mTOR basal activity levels.
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[each_answer] => D. Neither of the mice has any mTOR basal activity.
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[3] => Array
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[quiz_unique_key] => 1579828684
[question] => What does the data in Figure 1 suggest?
[value] => Array
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[answer] => 4
[description] => Reason for Correct Answer:
Figure 1 shows the results of eIF4EBP1 phosphorylation before and after supplementation with different BCAAs in the two mice. Pay attention to the error bars to see which change is significant.
According to the passage, phosphorylation of eIF4EBP1 by mTOR causes it to release the eIF4E that it has sequestered.This means that increased eIF4EBP1 phosphorylation corresponds to increased mTOR activity, decreased eIF4EBP1–eIF4E association, and increased eIF4E activity.
The graph shows that valine had an inhibitory effect on phosphorylation of eIF4EBP1 in mouse 2, if you compare the valine treatment to the control/baseline. This suggests that valine likely increased eIF4EBP1–eIF4E association, since this association is inhibited by phosphorylation.
The graph shows that, in both mice, only leucine significantly promoted the phosphorylation of eIF4EBP1. (Notice the error bars indicate that the isoleucine effect was not significant for mouse 2.)
This means that leucine increased eIF4EBP1 phosphorylation in both mice, and according to the passage, eIF4EBP1 phosphorylation increases eIF4E activity.
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[answers] => Array
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[0] => Array
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[each_answer] => A. More BCAAs had a significant stimulatory effect on mouse 2, compared with mouse 1.
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[each_answer] => B. In mouse 2, supplementation with valine results in decreased eIF4EBP1–eIF4E association.
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[each_answer] => C. In mouse 2, supplementation with isoleucine results in significantly increased mTOR activity.
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[each_answer] => D. In both mice, supplementation with leucine likely results in increased eIF4E activity.
)
)
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[quiz_unique_key] => 1498560436
[question] => If nutritional companies use the data presented in Figure 1 as a reason to take supplements, which of the following assumptions are they making?
I. Increases in eIF4EBP1 phosphorylation are due to BCAA activation of the mTOR pathway.
II. BCAAs are not activating alternative pathways that increase protein levels.
III. Increased eIF4EBP1 phosphorylation leads to increased protein levels.
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
The passage states that “studies in animal models have suggested that certain BCAAs are more effective than others in activating mTOR,” and it presents the data in Figure 1 as an example.
The significance of this data thus relies on the assumption that increases in eIF4EBP1 phosphorylation are actually due to BCAA activation of the mTOR pathway (I) (rather than being due to an alternative variable that wasn’t controlled for in the experiment).
Presenting the Figure 1 data as a reason to take supplements would also be based on the assumption that increases in mTOR activity actually result in increased muscle mass (III).
The fact that BCAA may activate other pathways that increase protein levels does not necessarily undermine the evidence that there is BCAA-mediation activation of the mTOR pathway that might contribute to muscle mass. II is therefore incorrect.
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[0] => Array
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[each_answer] => A. I and II only
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[each_answer] => B. I and III only
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[each_answer] => C. II and III only
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[each_answer] => D. I, II, and III
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[quiz_unique_key] => 3413571627
[question] => What additional finding would provide the best evidence that BCAA related changes to eIF4EBP1 phosphorylation are mTOR mediated?
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[answer] => 3
[description] => Reason for Correct Answer:
As mentioned in the passage, BCAAs activate mTOR, a kinase that phosphorylates eIF4EBP1.
In the context of mTOR, an agonist is a substance that promotes or enhances mTOR activity, leading to increased downstream signaling and cellular responses associated with mTOR activation. Similarly, an antagonist for mTOR would refer to a substance that inhibits or blocks mTOR activity, resulting in decreased downstream signaling.
You would expect the addition of an mTOR antagonist to reduce eIF4EBP1 phosphorylation, and the presence of mTOR to increase phosphorylation, hypothetically.
A significant reduction in the difference between the control and treatment groups resulting from an mTOR antagonist would indicate that the excess eIF4EBP1 phosphorylation is due to the engagement of mTOR by BCAAs (rather than through other mechanisms).
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[answers] => Array
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[0] => Array
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[each_answer] => A. The addition of an mTOR antagonist results in a significant decrease in the eIF4EBP1 phosphorylation levels in all the treatment groups.
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[each_answer] => B. The addition of an mTOR agonist results in a significant increase in the eIF4EBP1 phosphorylation levels in all the treatment groups.
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[each_answer] => C. The addition of an mTOR antagonist decreases observed differences in eIF4EBP1 phosphorylation between control and treatment groups.
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[each_answer] => D. The addition of an mTOR agonist causes more significant changes in eIF4EBP1 in mouse 1 than in mouse 2.
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Figure 1
