Molecular therapy : the journal of the American Society of Gene TherapySep 11, 2026

D-Amino Acid Prodrug DLMEH May Activate Cell Growth Pathway Through Sestrin2 to Improve Muscle Protein Production in Age-Related Muscle Loss

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 12, 2026

Abstract

D-leucine methyl ester hydrochloride (DLMEH) preserves gastrocnemius mass by 19.3% in a rat model of dexamethasone-induced muscle atrophy.

DLMEH directly binds Sestrin2 with a binding affinity of Kd 28.3 µM, comparable to L-leucine.
In human primary myotubes, DLMEH (100 µM) restores protein synthesis inhibited by dexamethasone by 58.2%, outperforming L-leucine (800 µM, 28.5%).
In a rat model, intravenous DLMEH (100 mg/kg/day for 14 days) maintains grip strength at 90% of normal levels and treadmill endurance at 85% of normal.
RNA sequencing indicates a 41.7% reversal of gene expression changes caused by dexamethasone, with significant enrichment in pathways related to mTOR signaling and ribosome biogenesis.
Safety profiling indicates a no-observed-adverse-effect level (NOAEL) of 2000 mg/kg with a therapeutic index greater than 30.

Simplified

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. Three orthogonal biophysical methods demonstrate that DLMEH directly binds Sestrin2 (Kd 28.3 μM), equivalent to L-leucine. Sestrin2 siRNA knockdown and rapamycin co-treatment confirm Sestrin2-dependent, mTORC1-specific activation. In human primary myotubes, DLMEH (100 μM) restores dexamethasone-suppressed protein synthesis by 58.2%, significantly exceeding L-leucine (800 μM, 28.5%). In a rat dexamethasone-induced atrophy model, intravenous DLMEH (100 mg/kg/day, 14 days) preserves gastrocnemius mass (19.3% rescue), grip strength (90% of normal), and treadmill endurance (85% of normal), all superior to oral L-leucine. RNA-seq reveals 41.7% reversal of dexamethasone-induced transcriptomic changes with enrichment in mTOR signaling, ribosome biogenesis, and oxidative phosphorylation. Safety profiling establishes NOAEL at 2000 mg/kg with therapeutic index greater than 30. DLMEH represents a first-in-class Sestrin2-targeting mTORC1 activator for sarcopenia.

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D-Amino Acid Prodrug DLMEH May Activate Cell Growth Pathway Through Sestrin2 to Improve Muscle Protein Production in Age-Related Muscle Loss

Abstract

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