Selective Small-Molecule AdipoR1 Agonist 3-Hydroxy Pterocarpan Salt (CDRI-1709S) Ameliorates Skeletal Muscle Atrophy

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Skeletal muscle atrophy is a common complication of metabolic disorders and chronic diseases with no current pharmacological treatments.
• Adiponectin receptors (AdipoR1/AdipoR2) are crucial for muscle metabolism and myogenesis, but selective agonists are lacking for clinical use.

Purpose of the Study:

• To identify and characterize CDRI-1709S, a novel small-molecule agonist selective for AdipoR1.
• To evaluate the myogenic and anti-atrophy efficacy of CDRI-1709S in vitro and in vivo.

Main Methods:

• A high-throughput screen identified CDRI-1709S as an AdipoR1 agonist.
• Adiponectin signaling pathways were analyzed in cell lines and myotubes.
• Myogenesis, fiber-type composition, and metabolic capacity were assessed.
• In vitro and in vivo models of muscle atrophy (dexamethasone and denervation) were used to evaluate anti-atrophy effects.

Main Results:

• CDRI-1709S selectively activated AdipoR1, inducing key signaling pathways (AMPK, AKT, p38-MAPK) and metabolic targets (PGC-1α, GLUT4, UCP3).
• It promoted myoblast differentiation and protected myotubes against atrophy by suppressing atrogenes (Atrogin-1, MuRF-1).
• In vivo studies demonstrated that CDRI-1709S restored muscle structure, signaling, and function in rat models of atrophy, improving grip strength and endurance.

Conclusions:

• CDRI-1709S is the first AdipoR1-selective small-molecule agonist with demonstrated myogenic and anti-atrophy effects.
• Targeting AdipoR1 represents a promising therapeutic strategy for sarcopenia and skeletal muscle atrophy.