Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression

TLDR

Skeletal muscle atrophy is a debilitating response to starvation and systemic diseases such as diabetes, cancer, and renal failure. The authors hypothesized that a common transcriptional program underlies muscle mass loss across these conditions. They performed cDNA microarray analyses on muscles from fasted mice, cancer‑cachectic rats, streptozotocin‑induced diabetic rats, uremic rats, and pair‑fed controls to compare mRNA changes. They identified a shared set of “atrogins” whose expression was altered in all four catabolic states, including up‑regulation of protein‑degradation genes and down‑regulation of ATP‑production, glycolysis, and extracellular‑matrix transcripts, indicating a common transcriptional program in diverse muscle atrophy types.

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.