Key result
Compound 1 inhibits MSTN-induced myotube atrophy and increases soleus mass and grip strength in mice.
Why the study?
Skeletal muscle atrophy is driven in part by unrestrained myostatin signaling, motivating the design of selective inhibitors.
Compound 1 is a promising lead prodrug for myostatin antagonism in skeletal muscle atrophy.
Answers are grounded in this paper and cite their sources.
Supports further development of myostatin prodomain mimetics; leaves open translation to human muscle atrophy therapies.
Skeletal muscle atrophy is driven in part by unrestrained myostatin (MSTN) signaling. We designed all-d tripeptide prodrug mimetics of the MSTN prodomain minimum active 23-mer fragment. Compounds 1 (H-d-Arg-d-Leu-d-Ala-OiPr) and 2 (H-d-Arg-d-Abu-d-Ala-OiPr) inhibited MSTN-induced myotube atrophy with sub-micromolar potency, while free-acid analogues (3, 4) and scrambled control (scr) were less active. All-d configuration conferred proteolytic stability exceeding 24 h. In vivo, compound 1 increased soleus mass and grip strength in mice. This work establishes compound 1 as a lead prodrug for MSTN antagonism in muscle atrophy.
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Shim et al. (2026) studied Skeletal muscle atrophy. Compound 1 (H-d-Arg-d-Leu-d-Ala-OiPr) vs. Free-acid analogues and scrambled control was evaluated on MSTN-induced myotube atrophy, soleus mass, and grip strength. Compound 1 (H-d-Arg-d-Leu-d-Ala-OiPr) inhibited MSTN-induced myotube atrophy with sub-micromolar potency and increased soleus mass and grip strength in mice.
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