Regulation of ATP-ubiquitin-dependent proteolysis in muscle wasting

― Protein breakdown plays a major role in muscle growth and atrophy. However, the regulation of muscle proteolysis by nutritional, hormonal and mechanical factors remains poorly understood. In this review, the methods available to study skeletal muscle protein breakdown, and our current understanding of the role of 3 major proteolytic systems that are well characterized in this tissue (ie the lysosomal, Ca 2 +-dependent and ATP-ubiquitin-dependent proteolytic pathways) are critically ana- lyzed. ATP-ubiquitin-dependent proteolysis is discussed in particular since recent data strongly suggest that this pathway may be responsible for the loss of myofibrillar proteins in many muscle-wasting conditions in rodents. In striking contrast to either the lysosomal or the Ca 2 +-dependent processes, ATP-ubiquitin-dependent protein breakdown is systematically influenced by nutritional manipulation (fast- ing and dietary protein deficiency), muscle activity and disuse (denervation atrophy and simulated weightlessness), as well as pathological conditions (sepsis, cancer, trauma and acidosis). The hormonal control of this pathway, its possible substrates, rate-limiting step, and functional associations with other proteolytic systems are discussed. skeletal muscle / protein breakdown / ubiquitin / proteasome Rsum ― Rgulation de la protolyse musculaire ATP-ubiquitine-dpendante au cours des tats cataboliques. La protolyse joue un rle majeur dans le contrle de la croissance ou de l'atro- phie musculaire. Cependant, ses mcanismes de rgulation par les nutriments, les facteurs hormonaux ou l'activit musculaire sont encore peu connus. Cette revue analyse de faon critique les diffrentes techniques disponibles pour tudier la dgradation des protines musculaires, et le rle des 3 systmes protolytiques majeurs bien caractriss dans ce tissu, c'est--dire la voie lysosomaie, Ca 2 +-dpen- dante et A TP-ubiquitine-dpendante. La protolyse A 7'P-uo;qu;f