Insulin inhibits protein breakdown at the whole body level, but neither the tissues nor the proteolytic pathways on which insulin exerts its antiproteolytic effect are well characterized. We measured the effects of insulin on mRNA levels for cathepsin D and m-calpain (a lysosomal and Ca2(+)-dependent proteinase, respectively) and ubiquitin (a component of ubiquitin-dependent proteolysis) in skeletal muscle, skin, liver, and intestine. We used a 6-h hyperinsulinemic, euglycemic, and hyperaminoacidemic clamp in goats, a species in which insulin markedly inhibited whole body protein breakdown under similar conditions [S. Tesseraud, J. Grizard, E. Debras, I. Papet, Y. Bonnet, G. Bayle, and C. Champredon. Am. J. Physiol. 265 (Endocrinol. Metab. 28): E402-E413, 1993]. Hyperinsulinemia and hyperaminoacidemia had no effect on cathepsin D, m-calpain, and ubiquitin mRNA levels in liver, skin, and jejunum. In contrast, depressed ubiquitin mRNA levels were seen in skeletal muscle without any concomitant reduction in mRNA levels for cathepsin D, m-calpain, and other components of the ubiquitin-dependent proteolytic pathway. The reduced ubiquitin mRNA levels in skeletal muscle may represent a possible mechanism explaining the antiproteolytic effect of insulin in vivo.
Summary ― 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 analyzed. 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
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