Abstract
The proteins in the skeletal muscle of mammals undergo a continuous process of synthesis and degradation, which regulates both the overall muscle protein mass and the levels of specific proteins. Increased proteolysis contributes to the muscle wasting seen in several pathological conditions (e.g. cancer, sepsis, diabetes, burn injury, trauma, etc.) and during fasting. Enhanced proteolysis in skeletal muscle, the major protein reservoir in the body, is a key metabolic adaptation providing the organism with free amino acids for energy production via gluconeogenesis and direct oxidation. Net mobilization of muscle protein in pathological situations also provides free amino acids for acute phase protein synthesis in the liver, and for protein synthesis in vital organs, like the brain and heart. The activation of the ubiquitin-proteasome pathway is mainly responsible for the muscle wasting that occurs in various animal models of cachexia. This pathway is also activated in human patients when muscle wasting is rapid and pronounced, but not in chronic situations such as muscular dystrophy or Cushing syndrome. This chapter presents a critical review of the mechanisms of ubiquitination and proteasome-dependent proteolysis, and then discusses the regulation of this proteolytic machinery in muscles, with emphasis on its nutritional and hormonal control.