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1

How does mTORC1 work??

Chelsey et al (1992) showed that res exercise induced increases in protein synthesis occurs concurrently with increase in RNA activity, therefore in response to physiologically relevant stimuli (i.e. Res ex) translation initiation is very active.

2

discuss Terzis et al (1999)??

Showed in a small sample (n=6), that mTOR activity correlates with resistance induced hypertrophy following 12 weeks of training (r=0.82)

3

Discuss Bodine et al (2001)???

Showed adding rapamycin essentially knocks out S6 kinase proving that the mTOR pathway is a crucial regulator in muscular hypertrophy and can prevent muscle atrophy in vivo.

4

Discuss the key mTOR paper, Drummond et al (2009)??

Verified the importance of mTOR for exercise induced MPS.

Gave 8 subjects 12mg of rapamycin and 7 subjects placebo.
Rapamycin had no changes in mixed muscle FSR, whereas control increased 40% from baseline following moderate intensity leg resistance exercise.

This only occurred in the early post ex period, by 2 hours it was back to a normal response (⬆️) for both mTORser2448 and S6K1thr389

5

Discuss the Goodman et al (2010) paper??

Showed in a Rheb (+) group there was more 'bigger' fibres (⬆️CSA by 64%).

We already know rheb activates mTOR signalling via a P13K/PKB independent mechanism and is sufficient to induce skeletal muscle hypertrophy.

6

What did Crozier (2005) highlight??

The reserve capacity of mTORC1 signalling.

Explains that only 30% of the maximum mTORC1 activity is required to fully saturate the MPS response.
Giving 10% leucine was not statistically different to giving 100% leucine in regards to protein synthesis.

7

Discuss Jacobs (2004) work on mTORC1??

Mechanically induced activation of mTORC1 occurs through an increase in rheb.

Eccentric contractions induce dissociation of TSC2 from the lysosome (EC 10% of control for intense colorized pixels)


Concluded the muscle lysosomes serve as a major regulatory centre for controlling mTOR signalling. In response to mechanical signalling events, mTOR signalling transitions to its active state

8

Discuss the role of PA I'm skeletal muscle (Hornberger et al, 2006)??

Acts as a signalling lipid, but also as a precursor for the biosynthesis of other lipids and binds to mTOR FRB domain and activates mTORC1

9

Discuss the work of You et al (2014)??

Showed overexpression of DAGK induces hypertrophy through an mTORC1 sensitive mechanism (in animals)

10

Discuss Joy et al (2014)???

Showed direct activation of mTORC1 through increased PA abundance in human muscle
750mg of daily PA supplementation improves the resistance training increase in CSA and 1RM following 8 weeks of training.

11

Discuss Dickinson et al (2011) when he looked at amino acid sensing and mTORC1 activation??

Showed mTOR is critical for AA driven muscle protein synthesis.

Post EAA, the control group was much higher than rapamycin group for FSR.
mTORSer2448 sig higher 2h post EAA compared to rapamycin
S6k1thr389 sig higher 1hr post EAA for controls compared to rapamycin

12

Discuss the Drummond et al (2010) paper??

When given 10g of EAA, muscle intracellular leucine increased from basal at 1,2 and 3h post feeding.

1h post feeding, LAT1mRNA was significantly increased from basal
3h post feeding, LAT1 protein was significantly increased from basal