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* Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA;
School of Nursing and Health Studies, Department of Human Science, Georgetown University, Washington, D.C., USA;
Pulmonary and Rehabilitation Research Group, Department of Medicine, University Hospital Aintree, Liverpool, UK;
Department of Physiological Sciences and Brain Research Institute, University of California, Los Angeles, California, USA; and
|| Renal Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
2Correspondence: Renal Unit, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, USA. E-mail: slecker{at}bidmc.harvard.edu or alfred_goldberg{at}hms.harvard.edu
We previously identified a common set of genes, termed atrogenes, whose expression is coordinately induced or suppressed in muscle during systemic wasting states (fasting, cancer cachexia, renal failure, diabetes). To determine whether this transcriptional program also functions during atrophy resulting from loss of contractile activity and whether atrogene expression correlates with the rate of muscle weight loss, we used cDNA microarrays and RT-polymerase chain reaction to analyze changes in mRNA from rat gastrocnemius during disuse atrophy induced by denervation or spinal cord isolation. Three days after Den or SI, the rate of muscle weight loss was greatest, and 78% of the atrogenes identified during systemic catabolic states were induced or repressed. Of particular interest were the large inductions of key ubiquitin ligases, atrogin-1 (35- to 44-fold) and MuRF1 (12- to 22-fold), and the suppression of PGC-1
and PGC-1ß coactivators (15-fold). When atrophy slowed (day 14), the expression of 92% of these atrogenes returned toward basal levels. At 28 days, the atrophy-inducing transcription factor, FoxO1, was still induced and may be important in maintaining the "atrophied" state. Thus, 1) the atrophy associated with systemic catabolic states and following disuse involves similar transcriptional adaptations; and 2) disuse atrophy proceeds through multiple phases corresponding to rapidly atrophying and atrophied muscles that involve distinct transcriptional patterns.—Sacheck, J. M., Hyatt, J-P. K., Raffaello, A., Jagoe, R. T., Roy, R. R., Edgerton, V. R., Lecker, S. H., Goldberg, A. L. Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases.
Key Words: atrogene • PGC-1 • ubiquitin • proteasome • muscle wasting • inactivity • muscle disease
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