Unravelling the Transcriptomic Symphony of Muscle Ageing: Key Pathways and Hub Genes Altered by Ageing and Caloric Restriction in Rat Muscle Revealed by RNA Sequencing
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ABSTRACT:
PROVIDER: PRJNA1075429 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27941049_1.fastq.gz | Fastqsanger.gz | |||
| SRR27941049_2.fastq.gz | Fastqsanger.gz | |||
| SRR27941050_1.fastq.gz | Fastqsanger.gz | |||
| SRR27941050_2.fastq.gz | Fastqsanger.gz | |||
| SRR27941051_1.fastq.gz | Fastqsanger.gz |
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Project description:Sarcopenia is a disease involving extensive loss of muscle mass and strength with age and is a major cause of disability and accidents in the elderly. Mechanisms purported to be involved in muscle ageing and sarcopenia are numerous but poorly understood, necessitating deeper study. Hence, we employed high-throughput RNA sequencing to explicate the global changes in protein-coding gene expression occurring in skeletal muscle with age. Caloric restriction (CR) is a proven prophylactic intervention against sarcopenia. Therefore, total RNA was isolated from the muscle tissue of both rats fed ad libitum and CR rats. Collected data were subjected to Gene Ontology, pathway, co-expression, and interaction network analyses. This revealed the functional pathways most activated by both ageing and CR, as well as the key “hub” proteins involved in their activation. RNA-seq revealed 442 protein-coding genes to be upregulated and 377 to be downregulated in aged muscle, compared to young muscle. Upregulated genes were commonly involved in protein folding and the immune response; meanwhile, downregulated genes were often related to developmental biology. CR was found to suppress 69.7% and rescue 57.8% of the genes found to be upregulated and downregulated in aged muscle, respectively. In addition, CR uniquely upregulated 291 and downregulated 304 protein-coding genes. Hub genes implicated in both ageing and CR included Gc, Plg, Irf7, Ifit3, Usp18, Rsad2, Blm and RT1-A2, whilst those exclusively implicated in CR responses included Alb, Apoa1, Ambp, F2, Apoh, Orm1, Mx1, Oasl2 and Rtp4. Hub genes involved in ageing but unaffected by CR included Fgg, Fga, Fgb and Serpinc1. In conclusion, this comprehensive RNA sequencing study highlighted gene expression patterns, hub genes and signalling pathways most affected by ageing in skeletal muscle. This data may provide the initial evidence for several targets for therapeutic interventions against sarcopenia.
2024-09-27 | GSE255551 | GEO
Project description:Healthy skeletal muscle can regenerate after ischaemic, mechanical, or toxin-induced injury, but ageing impairs that regeneration potential. This has been largely attributed to dysfunctional satellite cells and reduced myogenic capacity. Understanding which signalling pathways are associated with reduced myogenesis and impaired muscle regeneration can provide valuable information about the mechanisms driving muscle ageing and prompt the development of new therapies. To investigate this, we developed a high-throughput in vitro model to assess muscle regeneration in chemically injured C2C12 and human myotube-derived young and aged myoblast cultures. We observed a reduced regeneration capacity of aged cells, as indicated by an attenuated recovery towards preinjury myotube size and myogenic fusion index at the end of the regeneration period, in comparison with younger muscle cells that were fully recovered. RNA-sequencing data showed significant enrichment of KEGG signalling pathways, PI3K-Akt, and downregulation of GO processes associated with muscle development, differentiation, and contraction in aged but not in young muscle cells. Data presented here suggests that repair in response to in vitro injury is impaired in aged vs. young muscle cells. Our study establishes a framework that enables further understanding of the factors underlying impaired muscle regeneration in older age.
2023-07-05 | E-MTAB-12248 | biostudies-arrayexpress
Project description:Background Muscle ageing contributes to both loss of functional autonomy and increased morbidity. Muscle atrophy accelerates after 50 years of age, but the mechanisms involved are complex and likely result from the alteration of a variety of interrelated functions. In order to better understand the molecular mechanisms underlying muscle chronological ageing in human, we have undertaken a top-down differential proteomic approach to identify novel biomarkers after the fifth decade of age. Results Muscle samples were compared between adult (56 years) and old (78 years) post-menopausal women. In addition to total muscle extracts, low-ionic strength extracts were investigated to remove high abundance myofibrillar proteins and improve the detection of low abundance proteins. Two-dimensional gel electrophoreses with overlapping IPGs were used to improve the separation of muscle proteins. Overall, 1919 protein spots were matched between all individuals, 95 were differentially expressed and identified by mass spectrometry, and they corresponded to 67 different proteins. Our results suggested important modifications in cytosolic, mitochondrial and lipid energy metabolism, which may relate to dysfunctions in old muscle force generation. A fraction of the differentially expressed proteins were linked to the sarcomere and cytoskeleton (myosin light-chains, troponin T, ankyrin repeat domain-containing protein-2, vinculin, four and a half LIM domain protein-3), which may account for alterations in contractile properties. In line with muscle contraction, we also identified proteins related to calcium signal transduction (calsequestrin-1, sarcalumenin, myozenin-1, annexins). Muscle ageing was further characterized by the differential regulation of several proteins implicated in cytoprotection (catalase, peroxiredoxins), ion homeostasis (carbonic anhydrases, selenium-binding protein 1) and detoxification (aldo-keto reductases, aldehyde dehydrogenases). Notably, many of the differentially expressed proteins were central for proteostasis, including heat shock proteins and proteins involved in proteolysis (valosin-containing protein, proteasome subunit beta type-4, mitochondrial elongation factor-Tu). Conclusions This study describes the most extensive proteomic analysis of muscle ageing in humans, and identified 34 new potential biomarkers. None of them were previously recognized as differentially expressed in old muscles, and each may represent a novel starting point to elucidate the mechanisms of muscle chronological ageing in humans.
2015-02-19 | PXD001527 | Pride
Project description:We have previously documented a time-course of sarcopenia development in female C57Bl/6J mice, with significant loss of quadriceps muscle mass by 24 m that is more pronounced by 27-29 m. The present study used gastrocnemius muscles from female C57Bl/6J mice aged 3, 15, 24 and 29 months to investigate the expression of genes that coincide with, or potentially precede, muscle loss. The microarray analyses of ageing gastrocnemius muscle indicated that the Functional Theme Protein catabolism was first discernable in 15 and 24 age contrast and then again in the age contrast between 24 m and 29 m. A common Functional Theme in all age contrasts from the microarray analysis was extracellular matrix suggesting continual remodeling of skeletal muscle during ageing. Metabolic traits, particularly those involving altered fatty acid and glucose metabolism were apparent in the contrast between 24 m and 29 m. This may reflect inefficiency of lipid metabolism with ageing caused by altered mitochondrial function, which has been implicated in ageing processes in other studies. There were no functional themes associated with oxidative stress, inflammation or immune cell infiltration in any age contrast, likely indicating that these factors are not primary drivers of sarcopenia. Ageing was also associated with increased global gene expression variance, consistent with generalised decreased control of gene regulation. Microarray profiling was performed in gastrocnemius muscles from female C57Bl/6J mice aged 3, 15, 24 and 29 months.
2014-01-10 | E-GEOD-53959 | biostudies-arrayexpress
Project description:Muscle function relies on the precise architecture of dynamic contractile elements, which must be fine-tuned to maintain motility throughout life. Muscle is also highly plastic, and remodeled in response to stress, growth, neural and metabolic inputs. The evolutionarily conserved muscle microRNA, mir1, regulates distinct aspects of muscle biology during development, but whether it plays a role during ageing is unknown. Here we investigated the role of C. elegans mir-1 in muscle function in response to proteostatic stress during adulthood. mir-1 deletion results in improved mid-life muscle motility, pharyngeal pumping, and organismal longevity under conditions of polyglutamine repeat proteotoxic challenge. We identified multiple vacuolar ATPase subunits as subject to mir-1 control, and the regulatory subunit vha-13/ATP6VIA as a direct target downregulated via its 3’UTR to mediate mir-1 physiology. mir-1 further regulates nuclear localization of lysosomal biogenesis factor HLH-30/TFEB and lysosomal acidification. Our studies reveal that mir-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact muscle function and health during ageing.
2021-07-14 | PXD023544 | Pride
Project description:Age-related tissue alterations have been associated with a decline in stem cell number and function. Increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing. Here, using parallel single-cell transcriptome and DNA methylome profiling, we find a global increase of uncoordinated transcriptional heterogeneity and context-dependent alterations of DNA methylation heterogeneity in ageing mouse muscle stem cells. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. Notably, old cells diverging from young cells revealed alterations in the transcription of multiple extracellular matrix related genes. These findings show linked increases in heterogeneity between the epigenome and the transcriptome, with attendant degradation of coherent transcriptional networks and stem cell functional decline during ageing.
2019-08-22 | GSE121436 | GEO
Project description:Age-related tissue alterations have been associated with a decline in stem cell number and function. Increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing. Here, using parallel single-cell transcriptome and DNA methylome profiling, we find a global increase of uncoordinated transcriptional heterogeneity and context-dependent alterations of DNA methylation heterogeneity in ageing mouse muscle stem cells. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. Notably, old cells diverging from young cells revealed alterations in the transcription of multiple extracellular matrix related genes. These findings show linked increases in heterogeneity between the epigenome and the transcriptome, with attendant degradation of coherent transcriptional networks and stem cell functional decline during ageing.
2019-08-14 | GSE121364 | GEO
Project description:Although ageing is usually regarded as a high risk of cancer, the relationship between ageing stromal microenvironment and spontaneous cancer initiation is poorly understood. In murine models of DSS-induced colitis and AOM/DSS-induced colitis-associated cancer (CAC), we found ageing significantly inhibit both intestinal wound healing and simultaneous CAC initiation. In young mice, through conditional lineage tracing, a novel and important source of fibroblasts transformed from intestinal smooth muscle cells (ISMCs) was identified during intestinal wound healing, which existed persistently in CAC. We further found that activation of YAP/TAZ in ISMCs is required for their transformation into fibroblasts. However, in ageing intestinal microenvironment, the failure of YAP/TAZ activation in ISMCs led to reduced fibroblast numbers, orchestrating the inhibition of wound healing and simultaneous inhibition of CAC initiation. Collectively, our work revealed an important role of ageing stromal microenvironment in intestinal wound healing and CAC development. Meanwhile, our work also discovered an important source of fibroblasts involved in colitis and CAC.
2023-08-21 | GSE143693 | GEO
Project description:We have previously documented a time-course of sarcopenia development in female C57Bl/6J mice, with significant loss of quadriceps muscle mass by 24 m that is more pronounced by 27-29 m. The present study used gastrocnemius muscles from female C57Bl/6J mice aged 3, 15, 24 and 29 months to investigate the expression of genes that coincide with, or potentially precede, muscle loss. The microarray analyses of ageing gastrocnemius muscle indicated that the Functional Theme Protein catabolism was first discernable in 15 and 24 age contrast and then again in the age contrast between 24 m and 29 m. A common Functional Theme in all age contrasts from the microarray analysis was extracellular matrix suggesting continual remodeling of skeletal muscle during ageing. Metabolic traits, particularly those involving altered fatty acid and glucose metabolism were apparent in the contrast between 24 m and 29 m. This may reflect inefficiency of lipid metabolism with ageing caused by altered mitochondrial function, which has been implicated in ageing processes in other studies. There were no functional themes associated with oxidative stress, inflammation or immune cell infiltration in any age contrast, likely indicating that these factors are not primary drivers of sarcopenia. Ageing was also associated with increased global gene expression variance, consistent with generalised decreased control of gene regulation.
2014-01-10 | GSE53959 | GEO