Abstract
Advancements in animal models and cell culture techniques have been invaluable in the elucidation of the molecular mechanisms that regulate muscle atrophy. However, few studies have examined muscle atrophy in humans using modern experimental techniques. The purpose of this study was to examine changes in global gene transcription during immobilization-induced muscle atrophy in humans and then explore the effects of the most prominent transcriptional alterations on protein expression and function. Healthy men and women (N = 24) were subjected to two weeks of unilateral limb immobilization, with muscle biopsies obtained before, after 48 hours (48 H) and 14 days (14 D) of immobilization. Muscle cross sectional area (∼5%) and strength (10–20%) were significantly reduced in men and women (∼5% and 10–20%, respectively) after 14 D of immobilization. Micro-array analyses of total RNA extracted from biopsy samples at 48 H and 14 D uncovered 575 and 3,128 probes, respectively, which were significantly altered during immobilization. As a group, genes involved in mitochondrial bioenergetics and carbohydrate metabolism were predominant features at both 48 H and 14 D, with genes involved in protein synthesis and degradation significantly down-regulated and up-regulated, respectively, at 14 D of muscle atrophy. There was also a significant decrease in the protein content of mitochondrial cytochrome c oxidase, and the enzyme activity of cytochrome c oxidase and citrate synthase after 14 D of immobilization. Furthermore, protein ubiquitination was significantly increased at 48 H but not 14 D of immobilization. These results suggest that transcriptional and post-transcriptional suppression of mitochondrial processes is sustained throughout 14 D of immobilization, while protein ubiquitination plays an early but transient role in muscle atrophy following short-term immobilization in humans.
Highlights
Skeletal muscle atrophy is associated with bed rest, corticosteroid use, denervation, chronic renal failure, limb immobilization, neuromuscular disorders, sarcopenia of aging, and arthritis [1,2,3,4,5,6,7,8]
The genes corresponding to these probes were organized into functional categories, and the number of up-regulated and down-regulated genes within each functional category was compared to determine whether categories were generally up- or down-regulated during muscle atrophy (Figure 1 and S1)
All transcriptome changes were identical in both men and women, and an analysis of transcriptional alterations that were associated with strength decline did not yield any significantly altered probes
Summary
Skeletal muscle atrophy is associated with bed rest, corticosteroid use, denervation, chronic renal failure, limb immobilization, neuromuscular disorders, sarcopenia of aging, and arthritis [1,2,3,4,5,6,7,8]. Strong interest has focused on characterizing the fundamental molecular mechanism(s) underlying muscle atrophy and numerous cellular processes are known to coalesce into the overall atrophy phenotype These alterations include decreased protein synthesis, increased protein degradation, and suppression of bioenergetic pathways associated with mitochondrial function, and increased oxidative stress [9,10]. Reports concerning protein turnover in humans demonstrated that mixed muscle protein synthesis rates decline during muscle atrophy while protein degradation rates appear unchanged [22,23,24,25] This was confirmed in a recent study in which the rate of myofibrillar protein synthesis decreased by ,50% following 10 d of unilateral limb suspension (ULS) in human subjects [26]. The expression of atrogin-1 and MuRF-1 during muscle atrophy in humans is contentious, with some studies showing increased atrogin-1 and MuRF-1 mRNA, but not others [26,28,29,30,31]
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