Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy

TLDR

Muscle wasting, caused by fasting, inactivity, cancer, and other systemic diseases, results mainly from accelerated protein degradation via the ubiquitin‑proteasome pathway. The study aimed to identify key factors in muscle atrophy by comparing normal and atrophying muscles with cDNA microarrays, discovering a gene fragment highly induced in fasted mice. The identified gene encodes a protein with a functional F‑box domain that binds Skp1, Roc1, and Cul1 to form SCF-type ubiquitin‑protein ligases, and also contains nuclear localization and PDZ‑binding motifs. The cloned gene, named atrogin‑1, is specifically expressed in striated muscle, its mRNA rises in atrophying muscles from diabetes, cancer, renal failure, and even before atrophy onset, indicating it is a tissue‑specific F‑box protein that likely drives the enhanced proteolysis underlying muscle atrophy across diseases.

Abstract

Muscle wasting is a debilitating consequence of fasting, inactivity, cancer, and other systemic diseases that results primarily from accelerated protein degradation by the ubiquitin-proteasome pathway. To identify key factors in this process, we have used cDNA microarrays to compare normal and atrophying muscles and found a unique gene fragment that is induced more than ninefold in muscles of fasted mice. We cloned this gene, which is expressed specifically in striated muscles. Because this mRNA also markedly increases in muscles atrophying because of diabetes, cancer, and renal failure, we named it atrogin-1. It contains a functional F-box domain that binds to Skp1 and thereby to Roc1 and Cul1, the other components of SCF-type Ub-protein ligases (E3s), as well as a nuclear localization sequence and PDZ-binding domain. On fasting, atrogin-1 mRNA levels increase specifically in skeletal muscle and before atrophy occurs. Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases.