Question

5) During Resistance training mechanical stretch and strain lead to the accumulation of phosphatidic acid (PA) and allow Rheb to be disinhibited (activated).

a. What do these signals lead to, and what is the end result (adaptation)?

b. What may happen o this pathway if AMPK is also activated via something like aerobic exercise?

Answer 1

Skeletal muscles are plastic tissues that rapidly adapt to their mechanical environment

Increased load across a muscle, in resistance exercise results in a compensatory increase in muscle size and strength.

However this increase in size is more due to hypertrophy of existing cells than increase n cell numbers.

Resistance training also causes adaptive responses in other associated tissues like tendons, bones and the extra cellular matrix

There are 2 main mechanisms involved -

1. Increase in Rheb disinhibition -

The forced removal of TSC2 from Rheb activates mTORC1.

This is due to the phosphorylation of TSC2 on RxxRXXs/T residues which move it away from Rheb.

This allows Rheb to remain in the GTP bound state.

Simultaneously amino acid uptake and intracellular amino acid levels increase.

The extra amino acids stimulate the leucyl tRNA synthase (LRS) to act as a GTPase activating protein (GAP) towards RagC/D and GATOR (GAP Activity Towards Rags)2 blocks GATOR1 (the GAP of RagA/B) and the Ragulator GTP loads RagA/B and activates the complex.

The active Rag complex then binds to raptor and positions mTOR beside its activator GTP bound Rheb.

The resulting elevation of mTORC1 activity drives myofibrillar protein synthesis and eventually leads to an increase in muscle mass and strength.

2. Accumulation of phosphatidic acid PA

The second direct activator of mTORC1 associated with load-induced muscle hypertrophy is a glycerophospholipid known as phosphatidic acid (PA).

Mechanical loading of muscle results in increased production of PA and this is required for mTORC1 activation.

Phosphatidic acid results in marked increases in mTORC1 activity when provided exogenously or through the transgenic overexpression of the enzymes that synthesize PA

PA mediates mTORC1 activation through direct binding to the FKBP12-rapamycin binding domain of mTOR.

Rapamycin-sensitive mTOR is the key signalling node through which Resistance exercise induces hypertrophy.

AMPK activation -

AMPK is a metabolic checkpoint.

It activates catabolic processes and inhibits anabolic processes, in part, by negatively regulating mTORC1 signaling.

So mTORC1 and AMPK work in opposing ways in the regulation of cell growth and metabolism.

Because it inhibits mTORC1 signaling, AMPK inhibits protein synthesis and promotes autophagy by directly phosphorylating and activating ULK1.

ULK1 is a kinase that is involved with autophagy, particularly in response to amino acid withdrawal.

AMPK also modulates carbohydrate metabolism by increasing intracellular glucose levels and reduces lipid synthesis by inhibiting acetyl CoA carboxylase 1 (ACC1) and acetyl CoA carboxylase 2 (ACC2), fatty acid synthase (FAS), glycerol-3-phosphate acyltransferase (GPAT), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)