Atrogin1/MAFbx: what atrophy, hypertrophy, and cardiac failure have in common.

Proteins in cardiac and skeletal muscle cells, as in other cells, are continually being synthesized and degraded back to their constituent amino acids. Protein turnover in cardiac myocytes utilizes the same proteolytic systems as other eukaryotic cells: the ubiquitin-proteasome pathway, which catalyzes the rapid degradation of misfolded and regulatory proteins, and the lysosomal-autophagic system, which degrades organelles and aggregated proteins. These systems are of major importance in determining cardiac size and functional capacity. The overall rates of proteolysis in a cell and the degradation of individual components are precisely regulated. For example, cardiac hypertrophy occurs when overall rates of protein synthesis exceed overall rates of protein degradation; conversely cells decrease in mass when degradation rates exceed synthesis, as occurs in skeletal muscle with disuse, fasting, and many systemic diseases, including cardiac failure. In addition, the levels of individual proteins, whether they are enzymes, transcription factors, or components of the sarcomere, are determined in large part by their rates of ubiquitin-mediated degradation. In this issue of Circulation Research, Usui et al1 demonstrate how a single ubiquitination enzyme can have major effects on cardiac growth and function. In this pathway, proteins are targeted for degradation by the 26S proteasome by covalent attachment of a chain of ubiquitin molecules. This multistep pathway first involves the activation of the small protein ubiquitin by an enzyme, E1, which then transfers the highly reactive ubiquitin to one of the cell’s many ubiquitin-conjugating enzymes, E2s. A ubiquitin protein ligase, E3, then binds the protein substrate and the ubiquitin-E2 and catalyzes the formation of a chain of ubiquitins on the protein. Different E2-E3 pairs function in the degradation of different proteins, and the specificity of the E3s for specific groups of proteins provides exquisite selectivity to this degradation process. The content of different E2s and E3s varies between tissues and with different physiological conditions (as is nicely illustrated by the findings of Usui et al), but which E2s and E3s function normally in cardiac muscle is unknown. The human genome contains over 650 ubiquitin ligases, which makes possible precise regulation of different cell processes, and in recent years, dramatic progress has been made in elucidating the roles of different E3s in regulating metabolism, transcription, cell cycle, oncogenesis, and so forth. Although the pharmacological modulation of specific ubiquitin ligases is an attractive approach for treating many diseases, this possibility has thus far not been exploited, although an inhibitor of the proteasome (Bortezomib) is now widely used in the treatment for certain hematologic cancers. In this regard, it is intriguing that proteasome inhibitors also attenuate or reverse cardiac hypertrophy in multiple rodent models.2