title: Meta-analysis of expression signatures of muscle atrophy: gene interaction networks in early and late stages.
abstract: BACKGROUND
  Skeletal muscle mass can be markedly reduced through a process called atrophy, as a consequence of many diseases or critical physiological and environmental situations. Atrophy is characterised by loss of contractile proteins and reduction of fiber volume. Although in the last decade the molecular aspects underlying muscle atrophy have received increased attention, the fine mechanisms controlling muscle degeneration are still incomplete. In this study we applied meta-analysis on gene expression signatures pertaining to different types of muscle atrophy for the identification of novel key regulatory signals implicated in these degenerative processes.
  
  
  RESULTS
  We found a general down-regulation of genes involved in energy production and carbohydrate metabolism and up-regulation of genes for protein degradation and catabolism. Six functional pathways occupy central positions in the molecular network obtained by the integration of atrophy transcriptome and molecular interaction data. They are TGF-beta pathway, apoptosis, membrane trafficking/cytoskeleton organization, NFKB pathways, inflammation and reorganization of the extracellular matrix. Protein degradation pathway is evident only in the network specific for muscle short-term response to atrophy. TGF-beta pathway plays a central role with proteins SMAD3/4, MYC, MAX and CDKN1A in the general network, and JUN, MYC, GNB2L1/RACK1 in the short-term muscle response network.
  
  
  CONCLUSIONS
  Our study offers a general overview of the molecular pathways and cellular processes regulating the establishment and maintenance of atrophic state in skeletal muscle, showing also how the different pathways are interconnected. This analysis identifies novel key factors that could be further investigated as potential targets for the development of therapeutic treatments. We suggest that the transcription factors SMAD3/4, GNB2L1/RACK1, MYC, MAX and JUN, whose functions have been extensively studied in tumours but only marginally in muscle, appear instead to play important roles in regulating muscle response to atrophy.
authors.affiliation: Department of Biology, University of Ferrara, Ferrara, Italy. enrica.calura@unifi.it
authors.forename: Enrica
authors.initials: E
authors.lastname: Calura
authors.forename: Stefano
authors.initials: S
authors.lastname: Cagnin
authors.forename: Anna
authors.initials: A
authors.lastname: Raffaello
authors.forename: Paolo
authors.initials: P
authors.lastname: Laveder
authors.forename: Gerolamo
authors.initials: G
authors.lastname: Lanfranchi
authors.forename: Chiara
authors.initials: C
authors.lastname: Romualdi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D015854:Up-Regulation
chemical_list: D009124:Muscle Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta