Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Genome-wide analysis of denervation induced gene expression in mouse triceps surae muscle

ABSTRACT: Analysis of denervation induced regulation of muscle mass at gene expression level. The hypothesis tested in the present study was that the presence of MuRF1 contributes to the extent of gene expression changes observed in specific sets of genes during a challenge leading to muscle atrophy. Results provide important information on the response of triceps surae muscle to sciatic nerve resection (denervation), such as specific structural, metabolic, and neuromuscular junction associated genes, that may be influenced by MuRF1 during atrophy. Total RNA obtained from isolated triceps surae muscle subjected to 3 or 14 days post-denervation compared to nonsurgically treated littermate control muscles.

ORGANISM(S): Mus musculus

SUBMITTER: J. Furlow

PROVIDER: E-GEOD-44205 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Belt electrode-skeletal muscle electrical stimulation (B-SES) involves the use of belt-shaped electrodes to simultaneously contract multiple muscle groups. Twitch contractions have been demonstrated to protect against denervation-induced muscle atrophy in rats, possibly via mitochondrial biosynthesis. In this study, we examined whether inducing tetanus contractions with B-SES suppresses muscle atrophy and identified the underlying molecular mechanisms. We evaluated the effects of acute (60 Hz, 5 min) and chronic (60 Hz, 5 min, every alternate day for 1 week) B-SES on the tibialis anterior (TA) and gastrocnemius (GAS) muscles in Sprague Dawley rats using belt electrodes attached to both ankle joints. In acute stimulation, a significant decrease in glycogen content in the left and right TA and GAS was observed, suggesting that B-SES causes simultaneous contractions in multiple muscle groups. B-SES also enhanced p70S6K phosphorylation, an indicator of the mechanistic target of rapamycin complex 1 activity. During chronic stimulations, rats were divided into control (CONT), denervation-induced atrophy (DEN), and DEN+electrically stimulated with B-SES (DEN＋ES) groups. After 7 days of treatment, muscle wet weight (n = 8-11 for each group) and muscle fiber cross-sectional area (CSA, n = 6 for each group) of the TA and GAS muscles were reduced in the DEN and DEN+ES groups compared to those in the CON group. The DEN+ES group showed significantly higher muscle weight and CSA than the DEN group. Although RNA-seq and pathway analysis suggested that mitochondrial and ribosome biogenesis are key events in this phenomenon, mitochondrial content showed no difference. In contrast, ribosomal RNA 28S and 45S (n = 6) levels in the DEN+ES group were higher than those in the DEN group. The mRNA levels of the muscle proteolytic molecules Atrogin-1 and MuRF1 were significantly higher in DEN than in CONT but were suppressed in DEN+ES. In conclusion, tetanic electrical stimulation of both ankles using belt electrodes was effective in preventing denervation-induced atrophy in multiple muscle groups. Unlike twitch contractions, ribosomal biosynthesis plays a key role in tetanic contractions to prevent muscle atrophy.

Project description:Loss of muscle proteins and the consequent weakness has important clinical consequences in diseases such as cancer, diabetes, chronic heart failure and in ageing. In fact, excessive proteolysis causes cachexia, accelerates disease progression and worsens life expectancy. Muscle atrophy involves a common pattern of transcriptional changes in a small subset of genes named atrophy-related genes or atrogenes. Whether microRNAs play a role in the atrophy program and muscle loss is debated. To understand the involvement of miRNAs in atrophy we performed miRNA expression profiling of mouse muscles under wasting conditions such as fasting, denervation, diabetes and cancer cachexia. We found that the miRNA signature is peculiar of each catabolic condition. We then focused on denervation and we revealed that changes in transcripts and microRNAs expression did not occur simultaneously but were shifted. Indeed, while the transcriptional control of the atrophy-related genes peaks at 3 days, the changes of miRNA expression maximised at 7 days after denervation. Among the different miRNAs, microRNA-206 and 21 were the most induced in denervated muscles. We characterized their pattern of expression and defined their role in muscle homeostasis. Indeed, in vivo gain and loss of function experiments revealed that miRNA-206 and miRNA-21 were sufficient and required for atrophy program. In silico and in vivo approaches identified the transcription factor YY1 and the translational initiator factor eIF4E3 as downstream targets of these miRNAs. Thus miRNAs are important for the fine-tuning of the atrophy program and their modulation can be a novel potential therapeutic approach to counteract muscle loss and weakness in catabolic conditions. To determine which miRNAs are relevant for the atrophic process, we performed miRNA expression profiles of muscles from different atrophic models (starvation, denervation and streptozotocin-induced diabetes). We checked whether there was a common signature of miRNA expression in different atrophying conditions and we found that every catabolic situation require a peculiar pattern of miRNA. We further focus on the condition of denervation and identified the most up-regulated miRNAs in this condition, miRNA-206 and miRNA-21.

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Genome-wide analysis of denervation induced gene expression in mouse triceps surae muscle

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