Journal
FASEB JOURNAL
Volume 21, Issue 1, Pages 140-155Publisher
WILEY
DOI: 10.1096/fj.06-6604com
Keywords
atrogene; PGC-1; ubiquitin; proteasome; muscle wasting; inactivity; muscle disease
Categories
Funding
- NIAMS NIH HHS [R01 AR055255-02, F32 AR048517, R01 AR055255] Funding Source: Medline
- NIDDK NIH HHS [DK6230701] Funding Source: Medline
- NINDS NIH HHS [NS16333] Funding Source: Medline
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [F32AR048517, R01AR055255] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK062307] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P01NS016333] Funding Source: NIH RePORTER
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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 alpha and PGC-1 beta 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.
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