In space, the significant loss of muscle mass results primarily from an accelerated degradation of muscle proteins. Recently, a set of genes was identified that plays an important role in this activation of protein breakdown in atrophying muscles, and Dr. Alfred L. Goldberg and coworkers are identifying the mechanisms that activate this process. The goal of this research is to clarify the biochemical basis for this reaction and thus to develop pharmacological agents that reduce this excessive degradation and retard muscle wasting. This work has already led to the discovery of a new degradative enzyme, atrogin-1, that is specifically involved in muscle atrophy, including that seen in numerous disease states on Earth.
Overview
The Activation of Protein Breakdown in Muscle Upon Unloading and Possible Countermeasures
Principal Investigator:
Alfred L. Goldberg, Ph.D.
Organization:
Harvard Medical School
Technical Summary
The rapid loss of muscle mass that occurs in astronauts in space due to muscle unloading and in patients with many systemic diseases results primarily from accelerated degradation of muscle proteins. This enhancement of protein breakdown is mainly due to activation of the Ub-proteasome pathway. Our major goal is to clarify the biochemical basis for the activation of this proteolytic pathway and thus to develop pharmacological agents that reduce this excessive degradation and retard muscle wasting.
Recently, we identified a set of genes ("atrogenes") whose expression increases or decreases coordinately when muscles atrophy. In order to achieve a fuller understanding of the atrophy process and to develop novel inhibitors of the atrophy process, we plan to further study this transcriptional program and its regulation, especially after disuse. Of particular importance was the recent finding that the two genes induced most dramatically in atrophying muscles are the muscle-specific ubiquitin ligases (E3s), atrogin-1 (MAFbx) and MuRF1. If either of these enzymes is knocked out, the extent of muscle wasting is reduced. These Ub-ligases thus are very attractive therapeutic targets.
To fully understand the initiation of the atrophy process and to develop rational countermeasures, we are also studying the signal transduction systems that activate transcription of these genes in simple models of muscle atrophy in cultured myotubes. We recently found that the key factor in muscle hypertrophy, IGF-1, rapidly suppresses the expression of atrogin-1 and MuRF1, and prevents their induction by glucocorticoids. These effects of IGF-1 appear to be mediated by the PI3-kinase-AKT pathway, which probably inactivates one of the Forkhead transcription factors.
Our primary goal will be to identify the precise steps in this kinase cascade and the key transcription steps through which disuse and glucocorticoids activate and IGF-1 inhibits expression of atrogin-1 and MuRF1.
These studies should identify novel therapeutic targets (e.g. key kinases) or Foxo-regulatory factors whose inhibition blocks atrogin-1 and MuRF1 induction. Using these enzymes and "reporter gene" constructs, we shall screen libraries of small molecules for agents that prevent induction of atrogin-1 and MuRF1. Inhibiting the expression of these key ligases represents an exciting new therapeutic approach to prevent muscle wasting in space personnel and in diverse disease states. In addition, we are continuing to test whether inhibitors of proteasomes, both proved ones and the inhibitor (Velcade) now used in cancer therapy, by partially retarding overall proteolysis may be useful in retarding muscle wasting.
Earth Applications
If successful, this research may yield novel therapies to prevent or treat the marked wasting of muscle seen in various bed-ridden patients (i.e., the elderly) and ones with various systemic diseases (including cardiac failure, cancer, sepsis, renal failure and AIDS).
This project's funding ended in 2007