D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.

Shim JH, Lee JY, Ahn BK, Woo SW, Han J, Kim HS · 2026 · Molecular Therapy · Atlas ID SHIM2026

What this study shows

DLMEH, a D-leucine ester prodrug, binds Sestrin2 with leucine-like potency (Kd 28.3 uM, equivalent to L-leucine) and activates mTORC1 in a Sestrin2-dependent way. It restored protein synthesis in human myotubes and preserved muscle mass, grip strength and endurance in a rat dexamethasone-induced atrophy model (not an ageing sarcopenia model).

Abstract

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Sarcopenia, the age-related loss of skeletal muscle mass and function, lacks FDA-approved pharmacotherapy. The mechanistic target of rapamycin complex 1 (mTORC1), activated by leucine via Sestrin2, is the master regulator of muscle protein synthesis, but L-leucine suffers from rapid catabolism and poor bioavailability. Here, we report D-leucine methyl ester hydrochloride (DLMEH), a metabolically stabilized prodrug incorporating D-stereoisomer conversion, methyl esterification, and hydrochloride salt formation.

Read the full abstract on PubMed →

At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Rat (dexamethasone-induced muscle atrophy); human primary myotubes); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Rat (dexamethasone-induced muscle atrophy); human primary myotubes
Journal	Molecular Therapy
Year	2026
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1016/j.ymthe.2026.09.007 · PMID 42723280

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	D-leucine methyl ester hydrochloride (DLMEH) versus L-leucine; Sestrin2 siRNA knockdown; rapamycin co-treatment
Target	Sestrin2-dependent mTORC1 activation and muscle protein synthesis
Model	Rat (in vivo); human primary myotubes
Effect	DLMEH bound Sestrin2 with leucine-equivalent affinity and raised mTORC1-dependent protein synthesis, preserving muscle mass, grip strength and endurance in the rat atrophy model.

In the Atlas

Links in the pathway map

Supports Leucine inhibits Sestrin2

Cite this paper

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Shim, J. H., Lee, J. Y., Ahn, B. K., Woo, S. W., Han, J., & Kim, H. S. (2026). D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2026.09.007

@article{SHIM2026,
  author       = {Shim, J. H. and Lee, J. Y. and Ahn, B. K. and Woo, S. W. and Han, J. and Kim, H. S.},
  title        = {{D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia}},
  journal      = {Molecular Therapy},
  year         = {2026},
  doi          = {10.1016/j.ymthe.2026.09.007},
  note         = {PMID: 42723280},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record SHIM2026) [Data set]. https://mtor-atlas.org/study/SHIM2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_SHIM2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record SHIM2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/SHIM2026/},
  doi          = {10.5281/zenodo.22059963}
}

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