Abstract
BackgroundSkeletal 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.ResultsWe 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-β 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-β 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.ConclusionOur 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.
Highlights
Skeletal muscle mass can be markedly reduced through a process called atrophy, as a consequence of many diseases or critical physiological and environmental situations
We studied the enrichment of specific transcription factor (TF) binding sites in the genes relevant for atrophy as revealed by the meta-analysis, obtaining clues for important roles that should be ascribed in the atrophy processes to TF such as SP1, MAX and EEF1D/deltaEF1
Muscle atrophy can be induced by a variety of very diverse stimuli, there are a number of unexpected similarities among the intracellular responses that mediate the atrophic processes
Summary
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. Atrophy is a complex modification occurring in skeletal muscles as a result of a variety of causes such as damages to neural connections, disuse or unloading, fasting and as a consequence of many diseases including diabetes, sepsis, acidosis or cancer. The variety of conditions inducing atrophy implies different molecular triggers and signalling pathways for muscle wasting. The rate of synthesis of muscle contractile proteins is much higher than the rate of degradation that results in an increase of the size of the existing muscle fibers. On the contrary, enhanced protein breakdown is the primary cause of the rapid loss of muscle proteins that occurs during atrophy [1,2,3]
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