Exercise compensates the metformin on T2DM-indcued muscle atrophy through autophagy prominent FLNC degradation

FLNC is localized in the Z-disc of skeletal muscle and plays an important role in maintaining mechanical stability. Its degradation and renewal are specifically mediated by autophagy. Previously, we revealed that exercise is superior to metformin in improving muscle atrophy by promoting autophagy and inhibiting the proteasome. Building on this foundation, we aim to explore whether exercise can compensate for the deficiency of metformin in enhancing autophagy-mediated FLNC degradation. In this study, db/db mice were used to establish a model of type 2 diabetes mellitus (T2DM). An exercise intervention was conducted using a treadmill protocol at speeds of 7–12 m/min for 30–40 minutes per day, five days a week. Metformin was administered daily via gavage at a dose of 300 mg/kg. A combined intervention was performed, in which metformin was administered first, followed by exercise. After eight weeks of intervention, the ultrastructure of skeletal muscle was evaluated using electron microscopy. The key proteins HSP70, BAG3, LC3, LAMP2, and Cathepsin D involved in BAG3-mediated FLNC degradation via selective autophagy were quantified using Western blotting and immunofluorescence co-localization. We discovered that abnormalities in autophagy within skeletal muscle lead to metabolic disorders of FLNC in the Z-disc, contributing to the breakdown of myofibrillar structure. Furthermore, compared to metformin, exercise enhanced FLNC degradation by promoting BAG3-mediated selective autophagy, which may compensate for the limitations of metformin in combination treatment.