S‐Equol Alleviates Palmitic Acid–Induced Muscle Atrophy by Modulating the ERβ–AMPK–Autophagy Axis in L6 Cells

Abstract

Background Diabetic sarcopenia arises from metabolic imbalance–induced ROS accumulation and oxidative stress, which exacerbate muscle degeneration. Typically, autophagy removes excessive ROS and damaged organelles, helping to limit oxidative stress and preserve skeletal muscle function. S‐Equol (Eq), an intestinal metabolite of soy isoflavones with high affinity for estrogen receptor β (ERβ), exhibits estrogen‐like activity, yet its role in diabetic muscle atrophy remains unclear. Objectives This study investigated the effects of Eq on diabetic muscle atrophy in PA‐induced atrophic L6 myotubes. Methods Here, palmitic acid (PA)–treated L6 myotubes were used to model diabetes‐associated atrophy. Then, Eq treatment was further carried out, and oxidative stress, mitochondrial morphology, and autophagy were further detected. Results PA suppressed AMPK/ULK1‐mediated autophagy, induced ROS accumulation, disrupted mitochondrial morphology, and caused myotube atrophy. Eq treatment restored autophagic activity, significantly decreased ROS and malondialdehyde levels, maintained mitochondrial integrity and function, and preserved myotube structure. Importantly, inhibition of autophagy with 3‐MA abolished the protective effects of Eq, confirming that its antiatrophic actions are autophagy‐dependent. Mechanistically, knockdown of ERβ or AMPK prevented Eq from activating autophagy, suggesting that the ERβ–AMPK signaling axis is involved in Eq‐mediated autophagy regulation. Conclusions Our findings demonstrate that Eq alleviates PA‐induced myotube atrophy by promoting autophagy, potentially through modulation of the ERβ–AMPK signaling axis. These results highlight Eq as a potential nutritional therapy for the prevention and treatment of diabetic sarcopenia.