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.

Neuronal Protein 3.1 Deficiency Leads to Reduced Cutaneous Scar Collagen Deposition and Tensile Strength due to Impaired Transforming Growth Factor-β1 to -β3 Translation

“…Furthermore, we found that all three TGFbs are fibrogenic and placed P311 as a stimulator of fibrosis acting immediately upstream of TGF-b1 to -b3. Because P311 expression is up-regulated or down-regulated by hormones, 52 retinoic acid, 53 growth factors, 54 and mechanical tension, 4 and because P311 has proven to be decreased in muscular atrophy 55,56 and pulmonary emphysema, 6 it is likely that in pathologic conditions with decreased P311 expression scar formation will be affected in ways similar to those presented in this study, leading thereby to a higher risk of dehiscence.…”

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

“…Skeletal muscle atrophy could be due to reduced protein synthesis and/or increased protein catabolism due to targeted ubiquitination of muscle-specific proteins. Two muscle-specific E3 ligases, Atrogin1 and MuRF1, are up-regulated in skeletal muscle tissue in response to numerous atrophic signals [31][32][33]. Western blot analysis confirmed that there is increased ubiquitination of intracellular proteins in skeletal muscle tis-…”

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

“…E3 ligases, of which hundreds have been identified, confer substrate specificity (Glass, 2003a). During muscle atrophy, many of the genes encoding the Ub-proteasome pathway are upregulated , including E2 (such as E2 14K and UbcH2) and E3 (such as E3a / UBr1) genes (Li et al, 2003;Lecker et al, 2004). In particular, two E3 ubiquitin ligases, MuRF1 (muscle ring finger 1) and MAFbx (muscle atrophy F-box or atrogin-1) have been identified as mediators of muscle atrophy (Bodine et al, 2001a;Dehoux et al, 2003).…”