mTORC1 Signaling in Energy-Restricted States

The Central Role of mTORC1

The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine protein kinase that functions as the primary integrator of anabolic signalling in eukaryotic cells. In skeletal muscle, mTORC1 acts as a "master switch" regulating the balance between protein synthesis and protein degradation.

mTORC1 is activated by two major classes of stimuli: the presence of amino acids (particularly leucine) and mechanical/growth factor signalling (mediated through insulin, IGF-1, and the phosphoinositide 3-kinase/Akt pathway). When activated, mTORC1 phosphorylates downstream effectors including S6K1 and 4E-BP1, which enhance the rate of mRNA translation and thus myofibrillar protein synthesis.

During energy restriction, the systemic metabolic environment becomes unfavourable to mTORC1 activation. Circulating insulin and IGF-1 levels decline, amino acid availability may be reduced, and AMPK (which inhibits mTORC1 through TSC2 phosphorylation) is activated in response to low cellular energy charge.

Mechanotransduction and Mechanical Loading

Despite the systemic catabolic environment of energy deficit, mechanical loading of skeletal muscle can still activate mTORC1 through mechanisms independent of circulating growth factors. This is termed mechanotransduction—the conversion of mechanical force into intracellular signalling.

Several mechanotransduction pathways converge on mTORC1 activation during mechanical loading:

Stretch-activated ion channels: Mechanical tension opens ion channels, altering intracellular Ca²⁺ and Na⁺ concentrations, which activate downstream kinases including Akt and PKC.
Creatine phosphate depletion and ATP dynamics: Muscle contraction depletes phosphocreatine and temporarily reduces the ATP/ADP ratio, activating AMPK transiently but also triggering compensatory anabolic signalling to restore energy homeostasis.
Focal adhesion kinase (FAK): Mechanical stress activates FAK, which phosphorylates Akt and leads to mTORC1 activation independent of growth factors.

The result is that muscle tissue subjected to resistance exercise can maintain elevated mTORC1 signalling and myofibrillar protein synthesis rates even during systemic energy deficit, providing a protection against the catabolic state.

Leucine, Amino Acids, and mTORC1

Leucine, a branched-chain amino acid, is a potent and rapid activator of mTORC1. The mechanism involves the leucyl-tRNA synthetase (LRS) and sestrin2, which act as leucine sensors. When leucine is bound to LRS, it stimulates the release of GATOR2, which inhibits GATOR1, thereby releasing mTORC1 from inhibition.

During energy restriction, protein intake (and thus leucine availability) directly influences the degree of mTORC1 suppression. Inadequate amino acid provision exacerbates the catabolic state. Conversely, sufficient protein intake—particularly when combined with the mechanical stimulus from resistance training—can partially restore mTORC1 activity and anabolic signalling capacity.

The synergistic effect of mechanical loading and amino acid availability operates through this convergence: both pathways activate mTORC1, meaning their simultaneous presence produces amplified anabolic signalling compared to either stimulus alone.

Molecular Outcomes of mTORC1 Activation

Once activated, mTORC1 drives the following molecular events that favour anabolism:

S6K1 and S6 phosphorylation: mTORC1 phosphorylates and activates S6K1, which then phosphorylates the ribosomal S6 protein. This enhances translation initiation and elongation rates, directly increasing myofibrillar protein synthesis.
4E-BP1 phosphorylation and release of eIF4E: Phosphorylation of 4E-BP1 by mTORC1 causes it to release eIF4E, freeing the translation initiation factor to form the eIF4F complex, which is essential for cap-dependent mRNA translation.
Increased lipid synthesis: mTORC1 activates transcription factors (SREBP, PPARγ) that promote fatty acid and lipid biosynthesis, important for maintaining cell and organellar integrity during anabolism.
Suppression of autophagy: mTORC1 inhibits ULK1 (unc-51-like kinase 1), an autophagy initiator, thereby reducing basal autophagy rates and conserving cytoplasmic components.

Clinical and Research Significance

The preservation of mTORC1-mediated anabolic signalling during energy restriction through mechanical loading explains why resistance exercise is protective against muscle loss. Studies using muscle biopsy and phosphoproteomics have shown that resistance training performed during energy deficit maintains elevated phosphorylation of S6K1 and S6 compared to non-exercised conditions, correlating with better preservation of myofibrillar protein synthesis and muscle mass.