Global analysis of gene expression patterns during disuse atrophy in rat skeletal muscle

Abstract

Muscular inactivity leads to atrophy, weakness, and decreased fatigue resistance. In order to provide a window into the dynamic processes that underlie muscle atrophy, we performed global gene expression analysis of rat soleus muscles using Affymetrix GeneChips at 1, 4, 7 and 14 days of hindlimb unloading. Expression of 309 known genes was significantly changed by at least 2-fold (212 upregulated, 97 downregulated). K-means clustering was used to divide these genes into co-regulated clusters based on the similarity of temporal expression patterns. This allowed the development of a timeline of the atrophy process with respect to the behaviour of genes in a broad array of functional categories. Regulatory genes were often upregulated early, in either a transient or sustained manner, but they also populated clusters with later patterns of activation, suggesting different phases of molecular adaptations. Other early events were the activation of ubiquitination genes and downregulation of protein chaperones. In comparison, clusters representing slightly delayed activation patterns included genes involved in fast contraction, glycolysis, translational inhibition, oxidative stress, protein degradation, and amino acid catabolism. Downregulated genes exhibited fewer unique expression patterns and included structural and regulatory genes of the extracellular matrix and cytoskeleton, and genes that define a slow-oxidative phenotype. Other novel findings include the tight co-activation of proteasome subunit and ubiquitination genes, differential regulation of serine proteases and serine protease inhibitors, and the identification of transcriptional, signalling, growth and cell cycle genes that probably play a role in the atrophy process. The present work has uncovered temporal patterns of gene expression that highlight the molecular processes that underlie muscle atrophy and provide new avenues for study.

Hsp70 prevents disuse muscle atrophy in senescent rats

“…Our finding that endogenous Hsp70 is significantly decreased in the young, adult animals after 6 days of disuse is in agreement with previous studies using an immobilization model (Stevenson et al 2003;Selsby and Dodd 2005;Lawler et al 2006;Selsby et al 2007;Senf et al 2008). In addition, the immobilization-induced decreased Hsp70 in the senescent animals has not been demonstrated but is not surprising.…”

The Ubiquitin Ligase Nedd4-1 Participates in Denervation-Induced Skeletal Muscle Atrophy in Mice

“…Previously we, and others, have shown increased Nedd4-1 expression in gastrocnemius muscles undergoing denervation or unloading induced atrophy [15], [16], [30]. To confirm this phenomenon in our genetic mouse model, Nedd4-1 SMS-KO and littermate Myo Cre ;Nedd4-1 +/+ control mice underwent right tibial nerve transection with the left hind limb serving as control.…”

Hibernating squirrel muscle activates the endurance exercise pathway despite prolonged immobilization

“…We have demonstrated that during hibernation the 13-lined ground squirrel activates PGC-1α signaling in ways that are very similar to endurance exercise. Previous studies in rats have shown that hindlimb immobilization or muscle unloading is associated with a slow-to-fast fiber type transformation, resulting in a muscle profile more susceptible to fatigue (Fitts, et al, 2001, Stevenson, et al, 2003, Thorlund, et al, 2011). In contrast, we demonstrate that hibernating skeletal muscle exhibits a fiber type switch towards slow Type I muscle fibers and a concomitant decrease in fast Type IIB fibers.…”