Eicosapentaenoic Acid Attenuates Type 2 Diabetes Mellitus-Related Sarcopenia in Mice and Its Potential Mechanisms

This study investigated the therapeutic potential of eicosapentaenoic acid (EPA) against type 2 diabetes mellitus (T2DM)-related sarcopenia. In a streptozotocin/high-fat diet-induced T2DM mouse model, 24 week EPA supplementation improved insulin resistance, reduced advanced glycation end product (AGE) accumulation, and preserved skeletal muscle mass and strength. In vitro, the EPA mitigated high-glucose/AGE-induced atrophy in C2C12 myotubes. Mechanistically, EPA counteracted T2DM-related sarcopenia through improving insulin resistance and glycemic control, lowering AGE accumulation, and attenuating inflammatory response and oxidative damage in skeletal muscle. Moreover, EPA protected mitochondrial integrity in skeletal muscle cells by activating the AMPK/Sirt1/PGC-1α axis to boost mitochondrial biogenesis and alleviated excessive apoptosis via inhibiting the intrinsic apoptotic pathway. Furthermore, the EPA maintained protein metabolic homeostasis in skeletal muscle via restoring the PI3K/Akt/mTOR signaling cascade and suppressing the FoxO3a- and NF-κB-mediated ubiquitin-proteasome pathway. Overall, our findings suggest EPA as a promising nutritional intervention against T2DM-related sarcopenia.