Full mechanism, in text

Muscle protein synthesis

1 · Leu enters cytoplasm

After a meal with enough high-quality protein is digested, leucine reaches the muscle-cell cytoplasm, and it is the only amino acid that directly triggers .After a meal with enough high-quality protein (eggs, whey, lean meat) is digested and absorbed, free leucine (Leu) reaches the muscle-cell cytoplasm through the blood. A commonly quoted rule of thumb is about 2.5–3 g of leucine per meal (Volpi 2013 estimated about 3 g for older adults, equal to 25–30 g of high-quality protein).

Muscle cells hold a large free amino-acid pool, but only Leu is the direct trigger molecule for — the other (Ile, Val) play a supporting role, but Leu is the igniter. This is the chemical basis of the leucine threshold.

2 · Sestrin2 senses Leu

When Leu is high, it occupies the Sestrin2 pocket, making it release GATOR2 and setting off a chain that lifts the brake on the pathway.In the cytoplasm sits a sensor protein called Sestrin2 — its pocket binds Leu precisely.

· Low Leu: Sestrin2 holds the GATOR2 complex in a tight grip, keeping it caged → pathway off
· High Leu: Leu occupies Sestrin2's pocket → conformational change → GATOR2 released → GATOR2 inhibits GATOR1 → de-repression of the Rag GTPases

This is one of the body's most elegant nutrient-sensing mechanisms — a small molecule directly toggling the switch on protein synthesis.

3 · mTORC1 assembles on lysosome

Activated Rags recruit to the lysosomal membrane, where Rheb switches on its kinase activity; insulin is a permissive signal there, not a throttle.Once the Rag GTPases are activated, they recruit the complex ( + Raptor + mLST8) to the lysosomal membrane — where the second activator, Rheb GTPase, waits.

Rheb directly activates mTOR's kinase activity → mTORC1 can now phosphorylate downstream substrates.

Raptor acts as a scaffold, precisely aligning substrates with mTOR's active site — without Raptor, mTOR is a gun with no aim.

Insulin signalling (PI3K / Akt pathway) also converges here — but converging is not the same as adding up. The familiar claim that protein plus some carbohydrate builds more has been tested head-on: in Staples 2011, men did unilateral knee extensions and then took either 25 g of whey or 25 g of whey plus 50 g of maltodextrin, with muscle biopsies and stable-isotope tracers. The insulin area under the curve was 5 times that of the whey-only trial, and neither muscle protein synthesis nor breakdown differed at all.

Why? Because that protein dose had already driven synthesis to its ceiling. Insulin here is a permissive signal, not a throttle — it has to be present, but once it is sufficient, more of it buys nothing.

4 · Ribosomes translate → MPS

Activated phosphorylates S6K1 and 4E-BP1, so ribosomes launch translation en masse and build new protein chains, an effect from one meal lasting a few hours.Activated phosphorylates two key downstream substrates:
· S6K1 (p70 S6 kinase) → phosphorylates S6 → raises ribosomal translation efficiency
· 4E-BP1 → releases eIF4E → recruits mRNA to ribosomes to start translation

Result: muscle ribosomes launch translation en masse → new protein chains are synthesised → myofibrillar protein synthesis (MPS) thickens the fibres.

The synthesis one meal switches on lasts a few hours, then falls back. This is why:
· Split the day's protein across 3–4 meals so each clears the threshold (roughly 0.3–0.4 g/kg body weight as a rule of thumb)
· A protein-containing meal before and after training is enough: there is no 30-minute post-workout window, and keeping the two meals no more than about 3–4 hours apart will do (Aragon & Schoenfeld 2013)
· Morton 2018 (49 randomized trials) found that lean-mass gains stopped rising with total protein above about 1.6 g/kg/day (with a wide , 1.03–2.20); extra amino acids are mostly oxidized for fuel

Full mechanism, in text

1 · Leu enters cytoplasm

2 · Sestrin2 senses Leu

3 · mTORC1 assembles on lysosome

4 · Ribosomes translate → MPS

Leucine fires muscle synthesis

Full mechanism, in text

1 · Leu enters cytoplasm

2 · Sestrin2 senses Leu

3 · mTORC1 assembles on lysosome

4 · Ribosomes translate → MPS

Leucine fires muscle synthesis