Module 3 Flashcards
What are the three primary classes of signals that activate the mTOR pathway?
- Mechanical stress/force
- nutrient/amino acid availability (particularly leucine)
- growth factors (primarily insulin and IGF-1)
These signals are integrated by the mTORC1 protein complex.
What mechanical stimulus activates the mTORC1 pathway during muscle contraction?
Force pulling on the cell membrane
Stretching of the muscle can also contribute.
What is the role of α7β1 integrin in the mTORC1 activation pathway?
Binds to the extracellular matrix (ECM) and recruits focal adhesion kinase (FAK)
This binding leads to FAK activation.
What is the function of Insulin (AKT) in the mTORC1 signaling pathway?
Promotes mTORC1 signaling through disinhibition
AKT inhibits TSC1/2, relieving its inhibition on Rheb.
What activates the hippo (yap/taz) pathway?
- sarcomere sensors
- costameres
costameres are in the ECM and act on the nucleus
What effect does the Hippo pathway have on mTORC1 signaling?
YAP/TAZ promote mTORC1 signaling by suppressing PTEN
This enhances the PI3K/AKT pathway.
What is the relationship between intracellular leucine and GATOR2?
Intracellular leucine relieves the inhibition on GATOR2 by Sestrin2
This allows GATOR2 to activate GATOR1.
How do RagA/B GTPases contribute to mTORC1 activation?
Bind to the mTORC1 complex and promote its translocation to the lysosomal membrane
This is facilitated by their activation from GATOR1.
What stimuli activate the mTORC1 pathway via growth factors?
Binding of insulin and IGF-1 to their receptors
This activates the PI3K/AKT pathway.
Fill in the blank: mTORC1 acts as a central integrator of ________, amino acid availability, and growth factors.
mechanical stimuli
This integration promotes muscle protein synthesis and hypertrophy.
True or False: The Hippo pathway directly promotes the activation of mTORC1.
True
True or False: the yap/taz pathway affects leucine uptake
TRUE! it mediates LAT1 expression, helping with leucine uptake
What does mTORC1 translocate to after activation?
Lysosomal membrane
What does translational efficiency refer to?
Protein synthesis per unit RNA
How does mTOR enhance translational efficiency?
Influencing the initiation and elongation phases of translation
What is the role of p70S6K in protein synthesis?
Phosphorylates ribosomal protein S6 (rpS6)
What is the effect of phosphorylating rpS6?
Enhances translation of mRNAs encoding ribosomal proteins
What happens when mTOR phosphorylates 4EBP1?
Leads to its dissociation from eIF4E
What is eIF4E a component of?
eIF4F complex
What is the role of the eIF4F complex?
Binds to the 5’ cap of mRNA and recruits ribosomes
How does mTOR promote translation initiation?
By freeing eIF4E to form the active eIF4F complex
What is translational capacity determined by?
Total number of ribosomes present in the muscle cell
What is ribosome biogenesis?
Process by which new ribosomes are created
Where does ribosome biogenesis begin?
In the nucleus
What is transcribed to form pre-ribosomal RNA (pre-rRNA)?
Ribosomal DNA (rDNA)
What transcription factor is involved in ribosome biogenesis?
- c-Myc
What are the mature ribosomal RNA (rRNA) subunits produced?
- 40S rRNA
- 60S rRNA
What happens to mature rRNA subunits in the cytoplasm?
Combine to form mature, functional ribosomes
What indicates an increase in ribosome biogenesis post-exercise?
Increased pre-rRNA expression
How long does increased pre-rRNA expression last post-exercise?
Up to 48 hours
What is the effect of multiple bouts of resistance exercise on translational capacity?
Progressive increase in total number of ribosomes
How is translational capacity of muscle assessed?
Measuring total RNA content per unit tissue
What constitutes approximately 80% of the total RNA in the cell?
Ribosomal RNA (rRNA)
What is the overall role of mTOR in muscle hypertrophy?
Enhances efficiency of protein synthesis and promotes ribosome biogenesis
What is the myonuclear domain?
The amount of cell volume or sarcoplasm controlled by a single nucleus.
What happens to the myonuclear domain as muscle fibers hypertrophy?
The existing nuclei have a larger volume of cytoplasm and contractile proteins to support.
What is hypothesized about the myonuclear domain regarding hypertrophy?
There might be a limit to the size of this domain, necessitating the addition of more nuclei for continued hypertrophy.
How is myonuclear addition achieved?
Through the fusion of activated and differentiated satellite cells with existing myofibers, donating their nuclei.
What is the significance of myonuclear addition?
It helps maintain a relatively constant myonuclear domain size as the muscle fiber grows.
What difference is observed in myonuclear domains between muscle fiber types?
The myonuclear domain tends to be smaller in type I fibers compared to type II fibers.
What might explain the smaller myonuclear domain in type I fibers?
The higher metabolic demands of type I fibers.
What did studies using knockout satellite cells reveal about hypertrophy?
Hypertrophy can still occur with a reduced number of satellite cells or without myonuclear addition.
What was observed in normal mice during resistance running?
Hypertrophy occurred along with an expansion of the satellite cell pool and myonuclear addition.
What was the result of knocking out satellite cells in mice?
Muscle fibers still hypertrophied but to a lesser extent.
What negative consequences were noted from the absence of satellite cells?
Negative effects on extracellular matrix remodeling and capillarization.
What occurred when satellite cells were prevented from fusing with muscle fibers?
Satellite cells remained outside the myofiber but still released signaling molecules.
Since hypertrophy can still occur without myonuclear addition in the rodent model what does this imply?
The myonuclear domain may not be relevant unless we’re talking about extreme cases
* super huge bodybuilders
What recent research has highlighted about satellite cells?
Fusion-independent roles in muscle adaptation
Satellite cells play a role beyond direct fusion with muscle fibers.
What do satellite cells secrete that are involved in muscle adaptation?
Extracellular vesicles (exosomes)
These vesicles facilitate communication between satellite cells and muscle tissue.
What bioactive molecules are contained in the vesicles secreted by satellite cells?
Proteins and RNA, particularly microRNAs (miRNA)
An example of a protein is MP9, which is involved in ECM remodeling.
What type of signaling do the vesicles from satellite cells facilitate?
Paracrine signaling
This allows communication with neighboring myofibers and other muscle cells.
What is one role of the vesicles in relation to the extracellular matrix (ECM)?
Regulation of the ECM
This includes preventing fibrosis and organizing the ECM for efficient force transmission.
How do vesicles influence the muscle fiber environment?
By modulating it
This modulation can affect muscle fiber function and adaptation.
What type of regulation is influenced by microRNAs delivered by the vesicles?
Post-transcriptional regulation
MicroRNAs can affect the translation of mRNA into proteins within myofibers.
Fill in the blank: Satellite cells prevent _______ through their vesicle secretion.
fibrosis
Fibrosis refers to excessive collagen accumulation.
What does growth hormone do?
- builds ECM and collagen
- helps with fat loss
What does IGF-1 do?
activates MTOR
What are the two ways that testosterone increases hypertrophy
- genomic
- non-genomic
- direct increase in translation (but very smol)
What does it mean for testosterone to increase hypertrophy through genomic means?
binding to androgen receptors and enters cell as a complex
* transcription increases
* translation increases
What does it mean for testosterone to increase hypertrophy through NON-genomic means?
stimulates MTOR
