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(The FASEB Journal. 2004;18:39-51.)
© 2004 FASEB

Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression

STEWART H. LECKER1, R. THOMAS JAGOE*,1, ALEXANDER GILBERT, MARCELO GOMES{dagger}{dagger}, VICKIE BARACOS{dagger}, JAMES BAILEY{ddagger}, S. RUSS PRICE{ddagger}, WILLIAM E. MITCH§ and ALFRED L. GOLDBERG{dagger}{dagger},2

Renal Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;
* Pulmonary and Rehabilitation Research Group, Department of Medicine, University Hospital Aintree, Liverpool, L9 7AL, UK;
{dagger} Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, AB T6G 2M7, Canada;
{ddagger} Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA;
§ Department of Medicine, University of Texas Medical Branch, Galveston Texas, USA; and
{dagger}{dagger} Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

2Correspondence: Department of Biology, Harvard Med. School, Boston, MA 02115, USA. E-mail: Alfred_goldberg{at}hms.harvard.edu

Skeletal muscle atrophy is a debilitating response to starvation and many systemic diseases including diabetes, cancer, and renal failure. We had proposed that a common set of transcriptional adaptations underlie the loss of muscle mass in these different states. To test this hypothesis, we used cDNA microarrays to compare the changes in content of specific mRNAs in muscles atrophying from different causes. We compared muscles from fasted mice, from rats with cancer cachexia, streptozotocin-induced diabetes mellitus, uremia induced by subtotal nephrectomy, and from pair-fed control rats. Although the content of >90% of mRNAs did not change, including those for the myofibrillar apparatus, we found a common set of genes (termed atrogins) that were induced or suppressed in muscles in these four catabolic states. Among the strongly induced genes were many involved in protein degradation, including polyubiquitins, Ub fusion proteins, the Ub ligases atrogin-1/MAFbx and MuRF-1, multiple but not all subunits of the 20S proteasome and its 19S regulator, and cathepsin L. Many genes required for ATP production and late steps in glycolysis were down-regulated, as were many transcripts for extracellular matrix proteins. Some genes not previously implicated in muscle atrophy were dramatically up-regulated (lipin, metallothionein, AMP deaminase, RNA helicase-related protein, TG interacting factor) and several growth-related mRNAs were down-regulated (P311, JUN, IGF-1-BP5). Thus, different types of muscle atrophy share a common transcriptional program that is activated in many systemic diseases.—Lecker, S. H., Jagoe, R. T., Gilbert, A., Gomes, M., Baracos, V., Bailey, J., Price, S. R., Mitch, W. E., Goldberg, A. L. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression.


Key Words: ubiquitin–proteasome pathway • transcription




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