Aging and MicroRNA Expression in Human Skeletal Muscle
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE23527 | GEO | 2010/10/01
SECONDARY ACCESSION(S): PRJNA131783
REPOSITORIES: GEO
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Project description:A common characteristic of aging is the loss of skeletal muscle (sarcopenia) which can lead to falls and fractures. MicroRNAs (miRNA) are novel post-transcriptional modulators of gene expression with a potential role as a regulator of skeletal muscle mass and function. The purpose of this study was to profile miRNA expression patterns in aging human skeletal muscle using a miRNA array followed by in-depth functional and network analysis. Muscle biopsy samples from 36 men (young: 31±2; n=19; older: 73±3; n=17) were: 1) analyzed for the expression of miRNAs using a microRNA array 2) validated with Taqman quantitative real-time PCR assays, and 3) identified (and later validated) for potential gene targets using the bioinformatics knowledge base software, Ingenuity Pathways Analysis. We found that 18 miRNAs were differentially expressed in older humans (P<0.05 and >500 expression level). The Let-7 family members, Let-7b and Let-7e, were significantly elevated and further validated in older subjects (P<0.05). Functional and network analysis from Ingenuity determined that gene targets of the Let-7âs were associated with molecular networks involved in cell cycle control such as cellular proliferation and differentiation. We confirmed with real-time PCR that the mRNA expression of the cell cycle regulators, CDK6, CDC25A and CDC34 were downregulated in older subjects compared to the young (P<0.05). These data suggest that aging is characterized by an increased expression of Let-7 family members which may downregulate genes related to cellular proliferation. We propose that the increased Let-7 expression in older human muscle may be an indicator of impaired cell cycle function. We analyzed skeletal muscle biopsy samples from 19 young and 17 older male subjects that have participated in our previous and current research experiments. The subjects were not engaged in any regular exercise training at the time of the enrollment; however they were physically independent and overall healthy. Screening of subjects were performed with clinical history, physical exam, and laboratory tests including complete blood count with differential, liver and kidney function tests, coagulation profile, fasting blood glucose and oral glucose tolerance test, hepatitis B and C screening, HIV test, TSH, urinalysis, and drug screening. All subjects gave informed written consent before participating in the study, which was approved by the Institutional Review Board of the University of Texas Medical Branch (which is in compliance with the Declaration of Helsinki). Once recruited, a dual-energy X-ray absorptiometry (DEXA) scan (Hologic QDR 4500W, Bedford, MA) was performed to measure body composition and lean mass. Study design. All subjects were admitted to the Clinical Research Center the day prior to the experiment, were provided a standardized dinner and were studied following an overnight fast under basal conditions. Subjects were studied during the same time of day to avoid potential circadian changes and refrained from exercise 48h prior to study participation. A muscle biopsy was obtained from the vastus lateralis of the leg. The biopsy was performed using a 5 mm Bergström biopsy needle, under sterile procedure and local anesthesia (1% lidocaine). Muscle biopsy sample was immediately blotted and frozen in liquid nitrogen and stored at -80oC until analysis. The muscle biopsy sample was used for microRNA and gene analysis.
2010-10-01 | E-GEOD-23527 | biostudies-arrayexpress
Project description:The loss of skeletal muscle mass during aging is a significant health concern linked to adverse outcomes in older individuals. Understanding the molecular basis of age-related muscle loss is crucial for developing strategies to prevent or reverse this debilitating condition. Long non-coding RNAs (lncRNAs) are a largely uncharacterized class of biomolecules that have been implicated in cellular homeostasis and dysfunction across a wide variety of tissues and cell types. To identify lncRNAs that might contribute to skeletal muscle aging we screened for lncRNAs whose expression was altered in vastus lateralis muscle from older compared to young adults. We identified FRAIL1 as an aging-induced lncRNA with high abundance in human skeletal muscle. In a cohort of healthy young and older adults, skeletal muscle FRAIL1 was most strongly expressed in older females and negatively associated with measures of muscle strength and mass. Forced expression of FRAIL1 in mouse tibialis anterior muscle elicits a dose-dependent reduction in skeletal muscle fiber size that is independent of changes in muscle fiber type. Furthermore, this reduction in muscle size is dependent on an intact region of FRAIL1 that is highly conserved across non-human primates. Unbiased transcriptional and proteomic profiling of the effects of FRAIL1 expression in mouse skeletal muscle revealed widespread changes in mRNA and protein abundance that recapitulate age-related changes in pathways and processes that are known to be altered in aging skeletal muscle. Taken together, these findings shed light on the intricate molecular mechanisms underlying skeletal muscle aging and implicate FRAIL1 in the reduction of muscle mass during this process.
2024-02-24 | GSE249356 | GEO
Project description:Inadequate protein intake initiates an accommodative response with adverse changes in skeletal muscle function and structure. mRNA level changes due to short-term inadequate dietary protein might be an early indicator of accommodation. The aims of this study were to assess the effects of dietary protein and the diet-by-age interaction on the skeletal muscle transcript profile. Self-organizing maps were used to determine expression patterns across protein trials. 958 transcripts were differentially expressed (P<0.05) with diet and 853 had a diet-by-age interaction (P<0.05) using ANOVA. The results for diet alone revealed that P63 was associated with up-regulation of transcripts related to ubiquitin-dependent protein catabolism and muscle contraction and P63 and P94 resulted in up-regulation of transcripts related to apoptosis and down-regulation of transcripts related to cell differentiation; muscle and organ development; extracellular space; and responses to stimuli and stress. The diet-by-age expression patterns demonstrated that across the three protein trials transcripts related to protein metabolism were affected by age. Changes in skeletal muscle mRNA levels in the younger and older males to protein intake near or below the RDA are indicative of an early accommodative response. 5052 transcripts were determined as differentially expressed (P<0.05) between the younger and older males, of which 2556 met the False Discovery Rate correction (P=0.0081). The age-related changes in the transcript profile were consistent with aging skeletal muscle phenotypes including; mitochondrial dysfunction (UP- and DOWN-regulation), RNA splicing (UP), oxidative stress (UP), apoptosis (UP), and energy metabolism (DOWN). Experiment Overall Design: 22 healthy free-living younger (21-43 y, n=12) and older (63-79 y, n=10) males completed three controlled feeding trials with protein intakes of 63% (P63: 0.50 g/kg), 94% (P94: 0.75 g/kg), and 125% (P125: 1.00 g/kg) of the recommended dietary allowance (RDA). A fasting state vastus lateralis biopsy was taken from the dominant leg of each subject on day 12 of each trial following an overnight fast. Total RNA was isolated from the muscle samples using Tri-Reagent and the manufacture's protocol.
2008-10-26 | E-GEOD-9419 | biostudies-arrayexpress
Project description:We investigated age-related changes in the transcriptional profile of skeletal muscle in 5 month old (young) and 25 month old (old) C57BL/6NHsd mice using high density oligonucleotide arrays (22,690 transcripts probed). We identified 712 transcripts that are differentially expressed in young (5 month old) and old (25-month old) mouse skeletal muscle. Caloric restriction (CR) completely or partially reversed 87% of the changes in expression. Examination of individual genes revealed a transcriptional profile indicative of increased p53 activity in the older muscle. To determine whether the increase in p53 activity is associated with transcriptional activation of apoptotic targets, we performed RT-PCR on four well known mediators of p53-induced apoptosis: puma, noxa, tnfrsf10b and bok. Expression levels for these proapoptotic genes increased significantly with age (P<0.05), while CR significantly lowered expression levels for these genes as compared to control fed old mice (P<0.05). Age-related induction of p53-related genes was observed in multiple tissues, but was not observed in SOD2+/- and GPX4+/- mice, suggesting that oxidative stress does not mediate the observed age-related increase in expression. Western blot analysis confirmed that protein levels for both p21 and GADD45a, two established transcriptional targets of p53, were higher in the older muscle tissue. These observations support a role for p53-mediated apoptotic activity in mammalian aging. Keywords: aging, calorie restriction, muscle, p53
2006-12-01 | GSE6323 | GEO
Project description:Skeletal muscle aging is a major causative factor for disability and frailty in the elderly. Recent theories about the origins of the progressive impairment of skeletal muscle with aging emphasize a disequilibrium between damage and repair. Macrophages participate in muscle tissue repair first as pro-inflammatory M1 subtype and then as M2 anti-inflammatory subtype. However, information on macrophage presence in skeletal muscle is still sporadic and the effect of aging on different phenotypes remains unknown. In this study, we sought to characterize the polarization status of macrophages human skeletal muscle at different ages. We found that most macrophages in human skeletal muscle are M2, and that this number increased with advancing age. On the contrary, M1 macrophages decline with aging, making the total number of macrophages invariant with older age. Notably, M2 macrophages co-localized with increasing intermuscular adipose tissue (IMAT) in aging skeletal muscle. The mouse strain BALB/c, intrinsically M2-prone, showed increased IMAT and regenerating myofibers in skeletal muscle, accompanied by elevated expression of adipocyte markers and M2 cytokines. Collectively, we report that polarization of macrophages to the major M2 subtype is associated with IMAT, and propose that increased M2 in aged skeletal muscle may reflect active repair of aging-associated muscle damage.
2022-01-01 | GSE125481 | GEO
Project description:Inadequate protein intake initiates an accommodative response with adverse changes in skeletal muscle function and structure. mRNA level changes due to short-term inadequate dietary protein might be an early indicator of accommodation. The aims of this study were to assess the effects of dietary protein and the diet-by-age interaction on the skeletal muscle transcript profile. Self-organizing maps were used to determine expression patterns across protein trials. 958 transcripts were differentially expressed (P<0.05) with diet and 853 had a diet-by-age interaction (P<0.05) using ANOVA. The results for diet alone revealed that P63 was associated with up-regulation of transcripts related to ubiquitin-dependent protein catabolism and muscle contraction and P63 and P94 resulted in up-regulation of transcripts related to apoptosis and down-regulation of transcripts related to cell differentiation; muscle and organ development; extracellular space; and responses to stimuli and stress. The diet-by-age expression patterns demonstrated that across the three protein trials transcripts related to protein metabolism were affected by age. Changes in skeletal muscle mRNA levels in the younger and older males to protein intake near or below the RDA are indicative of an early accommodative response. 5052 transcripts were determined as differentially expressed (P<0.05) between the younger and older males, of which 2556 met the False Discovery Rate correction (P=0.0081). The age-related changes in the transcript profile were consistent with aging skeletal muscle phenotypes including; mitochondrial dysfunction (UP- and DOWN-regulation), RNA splicing (UP), oxidative stress (UP), apoptosis (UP), and energy metabolism (DOWN). Keywords: Age and dietary protein response
2008-09-22 | GSE9419 | GEO
Project description:We investigated age-related changes in the transcriptional profile of skeletal muscle in 5 month old (young) and 25 month old (old) C57BL/6NHsd mice using high density oligonucleotide arrays (22,690 transcripts probed). We identified 712 transcripts that are differentially expressed in young (5 month old) and old (25-month old) mouse skeletal muscle. Caloric restriction (CR) completely or partially reversed 87% of the changes in expression. Examination of individual genes revealed a transcriptional profile indicative of increased p53 activity in the older muscle. To determine whether the increase in p53 activity is associated with transcriptional activation of apoptotic targets, we performed RT-PCR on four well known mediators of p53-induced apoptosis: puma, noxa, tnfrsf10b and bok. Expression levels for these proapoptotic genes increased significantly with age (P<0.05), while CR significantly lowered expression levels for these genes as compared to control fed old mice (P<0.05). Age-related induction of p53-related genes was observed in multiple tissues, but was not observed in SOD2+/- and GPX4+/- mice, suggesting that oxidative stress does not mediate the observed age-related increase in expression. Western blot analysis confirmed that protein levels for both p21 and GADD45a, two established transcriptional targets of p53, were higher in the older muscle tissue. These observations support a role for p53-mediated apoptotic activity in mammalian aging. Experiment Overall Design: Animals were killed by cervical dislocation. Five different animals were used for each experimental group. All collected gastrocnemius tissue was then dissected, placed in a microcentrifuge tube, flash-frozen in liquid nitrogen, and stored at -80°C until processed for microarrays.
2007-11-13 | E-GEOD-6323 | biostudies-arrayexpress
Project description:Skeletal muscle holds an intrinsic capability of growth and regeneration both in physiological conditions and in case of injury. Chronic muscle illnesses, generally caused by genetic and acquired factors, lead to deconditioning of the skeletal muscle structure and function, and are associated with a significant loss in muscle mass. At the same time, progressive muscle wasting is a hallmark of aging. Given the paracrine properties of myogenic stem cells, extracellular vesicle-derived signals have been studied for their potential implication in both the pathogenesis of degenerative neuromuscular diseases and as a possible therapeutic target. In this study, we screened the content of extracellular vesicles from animal models of muscle hypertrophy and muscle wasting associated with chronic disease and aging. Analysis of the transcriptome, protein cargo and microRNAs (miRNAs) allowed us to identify a hypertrophic miRNA signature amenable for targeting muscle wasting, consisting of miR-1 and miR-208a. We tested this signature among others in vitro on mesoangioblasts (MABs), vessel-associated adult stem cells, and we observed an increase in the efficiency of myogenic differentiation. Furthermore, injections of miRNA-treated MABs in aged mice resulted in an improvement in skeletal muscle features, such as muscle weight, strength and cross-sectional area compared to controls. Overall, we provide evidence that the extracellular vesicle-derived miRNA signature we identified enhances the myogenic potential of myogenic stem cells.
2022-11-09 | PXD035446 | Pride
Project description:Human aging is associated with skeletal muscle atrophy and functional impairment (sarcopenia). Multiple lines of evidence suggest that mitochondrial dysfunction is a major contributor to sarcopenia. We evaluated whether healthy aging was associated with a transcriptional profile reflecting mitochondrial impairment and whether resistance exercise could reverse this signature to that approximating a younger physiological age. Skeletal muscle biopsies from healthy older (N = 25) and younger (N = 26) adult men and women were compared using gene expression profiling, and a subset of these were related to measurements of muscle strength. 14 of the older adults had muscle samples taken before and after a six-month resistance exercise-training program. Before exercise training, older adults were 59% weaker than younger, but after six months of training in older adults, strength improved significantly (P<0.001) such that they were only 38% lower than young adults. As a consequence of age, we found 596 genes differentially expressed using a false discovery rate cut-off of 5%. Prior to the exercise training, the transcriptome profile showed a dramatic enrichment of genes associated with mitochondrial function with age. However, following exercise training the transcriptional signature of aging was markedly reversed back to that of younger levels for most genes that were affected by both age and exercise. We conclude that healthy older adults show evidence of mitochondrial impairment and muscle weakness, but that this can be partially reversed at the phenotypic level, and substantially reversed at the transcriptome level, following six months of resistance exercise training. Keywords: resistance exercise, muscle, aging
2007-07-16 | GSE8479 | GEO
Project description:The loss of skeletal muscle strength mid-life in females is associated with the decline of estrogen. Here, we questioned how estrogen deficiency might impact the overall skeletal muscle phosphoproteome after contraction, as force production induces phosphorylation of several muscle proteins. Phosphoproteomic analyses of the tibialis anterior muscle after contraction in two mouse models of estrogen deficiency, ovariectomy (Ovariectomized [Ovx] vs Sham) and natural aging-induced ovarian senescence (Older Adult [OA] vs Young Adult [YA]), identified a total of 2,593 and 3,507 phosphopeptides in Ovx/Sham and OA/YA datasets, respectively. Further analysis of estrogen deficiency-associated proteins and phosphosites identified 66 proteins and 21 phosphosites from both datasets. Of these, 4 estrogen deficiency-associated proteins and 4 estrogen deficiency-associated phosphosites were significant and differentially phosphorylated or regulated, respectively. Comparative analyses between Ovx/Sham and OA/YA using Ingenuity Pathway Analysis (IPA) found parallel patterns of inhibition and activation across IPA-defined canonical signaling pathways and physiological functional analysis, which were similarly observed in downstream GO, KEGG, and Reactome pathway overrepresentation analysis pertaining to muscle structural integrity and contraction, including AMPK and calcium signaling. IPA Upstream regulator analysis identified MAPK1 and PRKACA as candidate kinases and calcineurin as a candidate phosphatase sensitive to estrogen. Our findings highlight key molecular signatures and pathways in contracted muscle suggesting that the similarities identified across both datasets could elucidate molecular mechanisms that may contribute to skeletal muscle strength loss due to estrogen deficiency.
2023-09-01 | PXD035171 | Pride