α-Ketoglutarate Ameliorates Sarcopenia in D-Galactose-Induced Aging Mice by Modulating Protein Homeostasis and Optimizing Mitochondrial Function.

Background/Objectives: Sarcopenia is an age-related condition marked by a progressive decline in muscle mass, weakened strength, and decreased physical performance in the elderly. Methods: In this research, we used D-galactose (D-gal)-induced 8-week-old male C57BL/6J mice to establish a sarcopenia model. This model was utilized to investigate the effect and potential mechanism of α-ketoglutaric acid (AKG), a key intermediate of the tricarboxylic acid cycle, on sarcopenia. Results: Our findings demonstrated that AKG significantly ameliorated muscle mass, exercise endurance, grip strength, and cold tolerance in D-gal-induced aging mice. AKG could regulate protein homeostasis, thereby enhancing the protein composition and size of myofibers in D-gal-induced aging mice. Additionally, AKG enhanced SOD activity in the skeletal muscle of D-gal-induced aging mice and scavenged reactive oxygen species (ROS) by activating the SIRT1/PGC-1α/Nrf2 pathway, thereby improving mitochondrial function. Conclusions: In conclusion, AKG combated sarcopenia by regulating protein homeostasis and optimizing mitochondrial function in skeletal muscle. This study provides a scientific foundation for developing therapeutic interventions using AKG to target muscle aging.