Transcriptional pathways associated with skeletal muscle disuse atrophy in humans

Abstract

Disuse atrophy is a common clinical phenomenon that significantly impacts muscle function and activities of daily living. The purpose of this study was to implement genome-wide expression profiling to identify transcriptional pathways associated with muscle remodeling in a clinical model of disuse. Skeletal muscle biopsies were acquired from the medial gastrocnemius in patients with an ankle fracture and from healthy volunteers subjected to 4-11 days of cast immobilization. We identified 277 misregulated transcripts in immobilized muscles of patients, of which the majority were downregulated. The most broadly affected pathways were involved in energy metabolism, mitochondrial function, and cell cycle regulation. We also found decreased expression in genes encoding proteolytic proteins, calpain-3 and calpastatin, and members of the myostatin and IGF-I pathway. Only 26 genes showed increased expression in immobilized muscles, including apolipoprotein (APOD) and leptin receptor (LEPR). Upregulation of APOD (5.0-fold, P < 0.001) and LEPR (5.7-fold, P < 0.05) was confirmed by quantitative RT-PCR and immunohistochemistry. In addition, atrogin-1/MAFbx was found to be 2.4-fold upregulated (P < 0.005) by quantitative RT-PCR. Interestingly, 96% of the transcripts differentially regulated in immobilized limbs also showed the same trend of change in the contralateral legs of patients but not the contralateral legs of healthy volunteers. Information obtained in this study complements findings in animal models of disuse and provides important feedback for future clinical studies targeting the restoration of muscle function following limb disuse in humans.

β - catenin is central to DUX4 -driven network rewiring in facioscapulohumeral muscular dystrophy

“…TP53 [16], JUNB [20,17], HIF1A [20], WNT3 [4], LMO3 [20], ANXA4 [5] and HSPB1 [22]. Gene Set Enrichment Analysis (GSEA) [23] on the intersection also implicated many FSHD associated processes, such as myogenesis [17] and regulation of the actin cytoskeleton [15], and pathways, including, p53 [16], Wnt [4], and VEGF [5] To identify genes implicated as rewiring specifically in FSHD, we also ran InSpiRe on two datasets each describing skeletal muscle gene expression during ageing (GSE5086 [24] and GSE9676 [25]), disuse atrophy (GSE5110 [26] and GSE8872 [27]) and other muscle diseases involving inflammation and wasting (GSE3307 [19], where juvenile dermatomyositis and limb-girdle muscular dystrophy type 2A datasets were independently analysed). Genes rewiring in these non-FSHD datasets were considered as secondary rewiring.…”

“…We also used human skeletal muscle studies into gene expression in muscle diseases other than FSHD (GSE3307 [19]), ageing (GSE5086 [24] and GSE9676 [25]) and atrophy (GSE5110 [26] and GSE8872 [27]). …”

Prevention of muscle wasting and osteoporosis: the value of examining novel animal models

“…Interactions among these pathways appear to be critical in promoting proteolysis during muscle disuse atrophy (Powers et al, 2011;Talbert et al, 2013), while reactive oxygen species (ROS) have been implicated as a primary trigger leading to proteolysis under disuse conditions (Powers et al, 2011;Talbert et al, 2013). Gene expression profiling of disused muscle has demonstrated both increases and decreases in the expression of numerous genes over time, indicating that a complex suite of biochemical changes occur simultaneously to induce muscle atrophy (Chen et al, 2007;Stevenson et al, 2003). It is beyond the scope of this Review to analyse all of the cellular pathways implicated in the progression of muscle disuse atrophy in depth, so readers are directed to several recent reviews on the topic (Bodine, 2013a;Brooks and Myburgh, 2014;Powers et al, 2011;Schiaffino et al, 2013).…”

Frogs and estivation: transcriptional insights into metabolism and cell survival in a natural model of extended muscle disuse

“…Lipids are still likely to be an essential fuel source during periods of estivation and/or fasting in C. alboguttata, although the liver and fat bodies are the most likely organs contributing to fatty acid metabolism, rather than skeletal muscle (22). Dramatic downregulation of energy metabolism pathways have been documented in clinical models of muscle disuse (5,6). Evidence suggests there is a shift in fuel metabolism away from fat oxidation toward an increased reliance on glucose, and that fat accumulates in atrophied muscles in place of muscle protein (reviewed in Ref.…”