title: Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression.
abstract: 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.
authors.affiliation: Renal Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Stewart H
authors.initials: SH
authors.lastname: Lecker
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Jagoe
authors.forename: Alexander
authors.initials: A
authors.lastname: Gilbert
authors.forename: Marcelo
authors.initials: M
authors.lastname: Gomes
authors.forename: Vickie
authors.initials: V
authors.lastname: Baracos
authors.forename: James
authors.initials: J
authors.lastname: Bailey
authors.forename: S Russ
authors.initials: SR
authors.lastname: Price
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009133:Muscular Atrophy / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016326:Extracellular Matrix Proteins; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D008668:Metallothionein; D044767:Ubiquitin-Protein Ligases; D009584:Nitrogen