Using RNA sequencing to examine age-dependent skeletal muscle transcriptome response to bed rest-induced atrophy, and age independent disuse-induced insulin resistance
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ABSTRACT:
PROVIDER: PRJNA450495 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR7007950.fastq.gz | Fastqsanger.gz | |||
| SRR7007960.fastq.gz | Fastqsanger.gz | |||
| SRR7007970.fastq.gz | Fastqsanger.gz | |||
| SRR7007980.fastq.gz | Fastqsanger.gz | |||
| SRR7007990.fastq.gz | Fastqsanger.gz |
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Project description:Short-term bed rest is used to simulate muscle disuse in humans. In our previous reports, we found that 5d of bed rest induced a ~4% loss of skeletal muscle mass in OLD (60-79 y) but not YOUNG (18-28 y) subjects. Identifying muscle transcriptional events in response to bed rest and age-related differences will help identify therapeutic targets to offset muscle loss in vulnerable older adult populations. Skeletal muscle dysregulation during bed rest in the old may be driven by alterations in molecules related to fibrosis, inflammation, and cell adhesion. This information may aide in the development of mechanistic-based therapies to combat muscle atrophy during short-term disuse. Short-term muscle disuse is also characterized by skeletal muscle insulin resistance, though this response is divergent across subjects. The mechanisms regulating inactivity-induced insulin resistance between populations that are more or less susceptible to disuse-induced insulin resistance are not known, and delineated by age. High Susceptibility participants were uniquely characterized with muscle gene responses described by a decrease in pathways responsible for lipid uptake and oxidation, decreased capacity for triglyceride export (APOB), increased lipogenesis (i.e., PFKFB3, FASN), and increased amino acid export (SLC43A1).
2019-02-18 | GSE113165 | GEO
Project description:To identify atrophy genes directly targeted by Bcl-3 transactivator at a genome wide level, we performed whole transcript expression array and ChIP-seq for muscles from weight bearing or 5-day hind limb unloaded mice. Genes that showed increased expression with unloading and a Bcl-3 peak in the promoter (from ChIP-seq data) were considered as Bcl-3 direct targets during disuse atrophy. Using ChIP array, we identified 241 direct targets for Bcl-3. Our data describe Bcl-3 as a global regulator both of the proteolysis and the change in energy metabolism that are essential components of muscle atrophy due to disuse. Disuse skeletal muscle atrophy was induced by hind limb unloading. Weight bearing (WB) or 5-day hind limb unloaded (HU) muscles were harvested for total RNA isolation and processed for whole transcript expression profiling. We chose to examine gene expression and Bcl-3 binding from 5-day unloaded muscles because our previous time course study of disuse atrophy suggested that most genes are differentially regulated at this time point, and thus, would best represent the time for Bcl-3 binding to the gene targets of the NF-kB transcriptional network.
2012-11-10 | E-GEOD-40578 | biostudies-arrayexpress
Project description:ObjectivesThe time course and magnitude of atrophic remodeling and the effects of an acute rehabilitation program on muscle atrophy are unclear. We sought to characterize bed rest-induced leg muscle atrophy and evaluate the safety and efficacy of an acute rehabilitation program.DesignPrespecified analysis of a randomized controlled trial.SettingSingle-center urban hospital.PatientsAdults (24-55 yr) randomized to 70 days of sedentary bed rest.InterventionsThe 11-day post-bed rest rehabilitation program consisted of low intensity exercise and progressed to increased aerobic exercise duration, plyometric exercises, and higher intensity resistance exercise.Measurements and main resultsUpper (rectus femoris, vastus lateralis, quadriceps, hamstrings, adductors) and lower leg (medial gastrocnemius, lateral gastrocnemius, and soleus) MRI scans were obtained once before, nine times during, and three times after bed rest to assess muscle cross-sectional area. The magnitude and rate of muscle atrophy and recovery were determined for each muscle. Nine participants completed 70 days of sedentary bed rest and an 11-day rehabilitation program. A total of 11,588 muscle cross-sectional area images were quantified. Across all muscles except the rectus femoris (no change), there was a linear decline during bed rest, with the highest atrophic rate occurring in the soleus (-0.33%/d). Following rehabilitation, there was rapid recovery in all muscles; however, the quadriceps (-3.74 cm2; 95% CI, -7.36 to -0.12; p = 0.04), hamstrings (-2.30 cm2; 95% CI, -4.07 to -0.54; p = 0.01), medial gastrocnemius (-0.62 cm2; 95% CI, -1.10 to -0.14; p = 0.01), and soleus (-1.85 cm2; 95% CI, -2.90 to -0.81; p < 0.01) remained significantly lower than baseline.ConclusionsBed rest results in upper and lower leg muscle atrophy in a linear pattern, and an 11-day rehabilitation program was safe and effective in initiating a rapid trajectory of muscle recovery. These findings provide important information regarding the design and refinement of rehabilitation programs following bed rest.
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Project description:Muscle atrophy is one of the main deleterious consequences of physical inactivity. Bed rest represents a unique model of physical inactivity and results in main changes in muscle metabolic function. However, our knowledge on the detrimental effects of bed rest still needs clarification. The aim of this study was to decipher the mechanisms involved in disuse muscle atrophy and the effects of different countermeasures in healthy men. A cross-over trial was designed, with each trial consisting in a 7-day ambulatory control period for baseline data collection, followed by 21 days head-down tilt bed rest with or without resistive vibration exercise only or combined with nutritional (protein) supplement as countermeasures. The changes in the Vastus lateralis muscle proteome collected in the eight volunteers were characterized using mass spectrometry-based label-free quantitative proteomics.
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Project description:Short-term muscle disuse induces significant muscle loss in older adults and in some reports may be more accelerated with aging. Identifying muscle transcriptional events in response to bed rest may help identify therapeutic targets to offset muscle loss. Therefore, we compared the muscle transcriptome between young and older adults after bed rest and identified candidate targets related to changes in muscle loss. RNA was sequenced (HiSeq, Illumina; DESeq, R) from muscle biopsies obtained from young [ n = 9; 23 yr (SD 3)] and older [ n = 18; 68 yr (SD 6)] adults before and after 5-day bed rest. Significantly altered pathways in both young and old subjects relating to mechanosensing and cell adhesion (Actin Cytoskeleton Signaling, ILK Signaling, RhoA Signaling, and Integrin Signaling) were altered (activation z score) to a greater extent in old subjects. Hepatic Fibrosis/Hepatic Stellate Cell Activation was the top regulated pathway significantly altered only in the old. Fifty-one differentially regulated genes were only altered in the young after bed rest and resembled a gene expression profile like that in the old at baseline. Inflammation and muscle wasting genes (CXCL2, GADD45A) were uniquely increased in the old after bed rest, and the macrophage gene MAFB decreased in the old and correlated with the change in leg lean mass. In summary, skeletal muscle dysregulation during bed rest in the old may be driven by alterations in molecules related to fibrosis, inflammation, and cell adhesion. This information may aid in the development of mechanistic-based therapies to combat muscle atrophy during short-term disuse. NEW & NOTEWORTHY Using RNA sequencing and bioinformatics approaches, we identified that older adult skeletal muscle was characterized by dysregulated pathways associated with fibrosis, inflammation (upregulated), and cell adhesion and mechanosensing (downregulated) pathways, with a subset of genes differentially regulated in old and young muscle after bed rest that may describe predisposition to muscle loss. Unique upregulated genes only expressed in old muscle after bed rest indicated increased inflammation and muscle wasting (CXCL2, GADD45A) and decreased MAFB correlated with the change in leg lean mass.
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Project description:The primary goal of this study was to determine the effect of metformin treatment during 5 days of bed rest in older adults and observe any residual effects of metformin treatment during recovery from this disuse period.
2023-11-22 | GSE224900 | GEO
Project description:Astronauts experience dramatic loss of muscle mass, decreased strength, and insulin resistance, despite performing daily intense physical exercise that would lead to muscle growth on Earth. Partially mimicking spaceflight, prolonged bed rest causes muscle atrophy, loss of force, and glucose intolerance. To unravel the underlying mechanisms, we employed highly sensitive single fiber proteomics to detail the molecular remodeling caused by unloading and inactivity during bed rest and changes of the muscle proteome of astronauts before and after a mission on the International Space Station. Muscle focal adhesions, involved in fiber-matrix interaction and insulin receptor stabilization, are prominently downregulated in both bed rest and spaceflight and restored upon reloading. Pathways of antioxidant response increased strongly in slow but not in fast muscle fibers. Unloading alone upregulated markers of neuromuscular damage and the pathway controlling EIF5A hypusination. These proteomic signatures of mechanical unloading in muscle fiber subtypes contribute to disentangle the effect of microgravity from the pleiotropic challenges of spaceflight.
| S-EPMC9896895 | biostudies-literature
Project description:A mechanistic understanding of the age-related impairment to skeletal muscle regrowth following disuse atrophy as well as therapies to augment recovery in the aged are currently lacking. Mechanotherapy in the form of cyclic compressive loading has been shown to benefit skeletal muscle under a variety of paradigms, but not during the recovery from disuse in aged muscle. To determine whether mechanotherapy promotes extracellular matrix (ECM) remodeling, a critical aspect of muscle recovery after atrophy, we performed single cell RNA sequencing (scRNA-seq) of gastrocnemius muscle cell populations, stable isotope tracing of intramuscular collagen, and histology of the ECM in adult and aged rats recovering from disuse, with and without mechanotherapy. ECM remodeling-related gene expression in fibro-adipose progenitor cells (FAPs) was absent in aged compared to adult muscle following 7 days of recovery, and instead were enriched in chemoattractant genes. There was a significantly lower expression of genes related to phagocytic activity in aged macrophages during recovery, despite enriched chemokine gene expression of numerous stromal cell populations, including FAPs and endothelial cells. Mechanotherapy reprogrammed the transcriptomes of both FAPs and macrophages in aged muscle recovering from disuse to restore ECM-and phagocytosis-related gene expression, respectively. Stable isotope labeling of intramuscular collagen and histological evaluation confirmed mechanotherapy-mediated remodeling of the ECM in aged muscle recovering from disuse. In summary, our results highlight mechanisms underlying age-related impairments during the recovery from disuse atrophy and promote mechanotherapy as an intervention that reprograms the muscle transcriptional environment more similar to that of adult skeletal muscle.
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Project description:Disuse atrophy is a common clinical phenomenon which significantly impacts muscle function and activities of daily living. In this study, we did expression profiling to identify transcriptional pathways associated with muscle remodeling in a clinical model of disuse. Keywords: Differentiation design 28 Skeletal muscle biopsies from the medial gastrocnemius in patients with an ankle fracture (4 patients, 8 profiles) and from healthy volunteers (2 subjects, 4 profiles) subjected to 4-11 days of mobilization, as well as from the non-immobilized contralateral legs (16 profiles).
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