The study identifies a muscle-specific F-box protein named atrogin-1, which is highly expressed during muscle atrophy. Atrogin-1 is induced more than ninefold in fasted mice and in muscles affected by diabetes, cancer, and renal failure. It contains a functional F-box domain that binds to Skp1, allowing it to form an SCF-type Ub-protein ligase (E3). The protein also has a nuclear localization sequence and a PDZ-binding domain. Atrogin-1 mRNA levels increase specifically in skeletal muscle before atrophy occurs, suggesting its role in initiating and maintaining accelerated proteolysis. The findings indicate that atrogin-1 is a critical component in the enhanced proteolysis leading to muscle atrophy in various diseases.The study identifies a muscle-specific F-box protein named atrogin-1, which is highly expressed during muscle atrophy. Atrogin-1 is induced more than ninefold in fasted mice and in muscles affected by diabetes, cancer, and renal failure. It contains a functional F-box domain that binds to Skp1, allowing it to form an SCF-type Ub-protein ligase (E3). The protein also has a nuclear localization sequence and a PDZ-binding domain. Atrogin-1 mRNA levels increase specifically in skeletal muscle before atrophy occurs, suggesting its role in initiating and maintaining accelerated proteolysis. The findings indicate that atrogin-1 is a critical component in the enhanced proteolysis leading to muscle atrophy in various diseases.