Limb Immobilization Induces a Coordinate Down-Regulation of Mitochondrial and Other Metabolic Pathways in Men and Women

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.

REDD2 expression in rat skeletal muscle correlates with nutrient-induced activation of mTORC1: responses to aging, immobilization, and remobilization

“…Increased expression of the atrogenes, MAFbx and MuRF1, is considered to be an early marker of disuse atrophy (1,35,54) because expression of the mRNAs encoding the proteins is rapidly induced after limb immobilization in association with loss of muscle mass (8,22). The results of the present study showing that, in 2-mo-old rats, expression of both MAFbx and MuRF1 mRNA is upregulated after 7 days of hindlimb immobilization is in agreement with these previous reports.…”

Physical exercise and sarcopenia in older people: position paper of the Italian Society of Orthopaedics and Medicine (OrtoMed)

“…Exercise induces transient transcriptional activation of the PGC-1α gene in skeletal muscle, preserving muscle quality and aerobic capacity in aging (40). Increased muscle mitochondrial content and/or improved mitochondrial function following aerobic exercise lead to improved metabolic control, resulting in reduced oxidative stress and optimized exercise capacity (41,42). Muscle-specific PGC-1α knockout mice, which display impaired mitochondrial biogenesis, experience accelerated sarcopenia with aging (43).…”

Svak kobling mellom kronisk utmattelsessyndrom og pyruvat dehydrogenasemangel

“…It is well known that genes associated with the entire energy metabolism (including pyruvate dehydrogenase complex) are changed by immobilisation (10). Musculature grows and dwindles depending on the activity level; different expression patterns between the two groups in this study are therefore only to be expected.…”