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Comprehensive analysis of circular RNA profiles in skeletal muscles of aging mice and after aerobic exercise intervention.

ABSTRACT: Aging induces gradual accumulation of damages in cells and tissues, which leads to physiological dysfunctions. Aging-associated muscle dysfunction is commonly seen in aged population and severely affects their physical activity and life quality, against which aerobic training has been shown to exert antagonizing or alleviating effects. Circular RNAs (circRNAs) play important roles in various physiological processes, yet their involvement in aging-associated muscle dysfunction is not well understood. In this study, we performed comprehensive analysis of circRNAs profiles in quadriceps muscles in sedentary young and aging mice, as well as aging mice with aerobic exercise using RNA sequencing. Our results identified circRNAs altered by factors of aging and aerobic exercise. Their host genes were then predicted and analyzed by gene ontology enrichment analysis. Importantly, we found that circBBS9 featured decreased levels in aging compared to young mice and elevated expression in exercise versus sedentary aging mice. Besides, we performed GO and KEGG analysis on circBBS9 target genes, as well as established the circBBS9-miRNA-mRNAs interaction network. Our results indicate that circBBS9 may play active roles in muscle aging by mediating the benefits of aerobic training intervention, thus may serve as a novel therapeutic target combating aging-associated muscle dysfunction.

SUBMITTER: Guo M

PROVIDER: S-EPMC7138574 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Comprehensive analysis of circular RNA profiles in skeletal muscles of aging mice and after aerobic exercise intervention.

Guo Mingwei M Qiu Jin J Shen Fei F Wang Sainan S Yu Jian J Zuo Hui H Yao Jing J Xu Sainan S Hu Tianhui T Wang Dongmei D Zhao Yu Y Hu Yepeng Y Shen Feixia F Ma Xinran X Lu Jian J Gu Xuejiang X Xu Lingyan L

Aging 20200317 6

Aging induces gradual accumulation of damages in cells and tissues, which leads to physiological dysfunctions. Aging-associated muscle dysfunction is commonly seen in aged population and severely affects their physical activity and life quality, against which aerobic training has been shown to exert antagonizing or alleviating effects. Circular RNAs (circRNAs) play important roles in various physiological processes, yet their involvement in aging-associated muscle dysfunction is not well underst ...[more]

PMID: 32182212

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Project description:BackgroundCircular RNAs (circRNAs) have been shown to play important regulatory roles in a range of both pathological and physiological contexts, but their functions in the context of skin aging remain to be clarified. In the present study, we therefore, profiled circRNA expression profiles in four pairs of aged and non-aged skin samples to identify identifying differentially expressed circRNAs that may offer clinical value as biomarkers of the skin aging process.MethodsWe utilized an RNA-seq to profile the levels of circRNAs in eyelid tissue samples, with qRT-PCR being used to confirm these RNA-seq results, and with bioinformatics approaches being used to predict downstream target miRNAs for differentially expressed circRNAs.ResultsIn total, we identified 571 circRNAs with 348 and 223 circRNAs being up and downregulated that were differentially expressed in aged skin samples compared to young skin samples. The top 10 upregulated circRNAs in aged skin sample were hsa_circ_0123543, hsa_circ_0057742, hsa_circ_0088179, hsa_circ_0132428, hsa_circ_0094423, hsa_circ_0008166, hsa_circ_0138184, hsa_circ_0135743, hsa_circ_0114119, and hsa_circ_0131421. The top 10 reduced circRNAs were hsa_circ_0101479, hsa_circ_0003650, hsa_circ_0004249, hsa_circ_0030345, hsa_circ_0047367, hsa_circ_0055629, hsa_circ_0062955, hsa_circ_0005305, hsa_circ_0001627, and hsa_circ_0008531. Functional enrichment analyses revealed the potential functionality of these differentially expressed circRNAs. The top 3 enriched gene ontology (GO) terms of the host genes of differentially expressed circRNAs are regulation of GTPase activity, positive regulation of GTPase activity and autophagy. The top 3 enriched KEGG pathway ID are Lysine degradation, Fatty acid degradation and Inositol phosphate metabolism. The top 3 enriched reactome pathway ID are RAB GEFs exchange GTP for GDP on RABs, Regulation of TP53 Degradation and Regulation of TP53 Expression and Degradation. Six circRNAs were selected for qRT-PCR verification, of which 5 verification results were consistent with the sequencing results. Moreover, targeted miRNAs, such as hsa-miR-588, hsa-miR-612, hsa-miR-4487, hsa-miR-149-5p, hsa-miR-494-5p were predicted for circRna-miRna interaction networks.ConclusionOverall, these results offer new insights into circRNA expression profiles, potentially highlighting future avenues for research regarding the roles of these circRNAs in the context of skin aging.

Project description:Introduction: Gefitinib is a selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) widely used in lung adenocarcinoma (LUAD) patients harboring sensitive EGFR mutations. Although it has a good initial efficacy, acquired resistance to gefitinib is eventually inevitable. Studies have shown that circular RNA (circRNA) is involved in the development of acquired resistance to different anti-cancer drugs, but the comprehensive analysis of its expression profile and functions on acquired gefitinib resistance remains poor. Methods: To explore the aberrant circRNAs expression profiles, we collected peripheral plasma samples from 4 gefitinib-sensitive and 4 gefitinib-resistant patients for performing microarray analysis. Candidates of differentially expressed circRNAs were used and analyzed by bioinformatics modalities including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and a constructed circRNA-microRNA RNA network. The differential expression of selected circRNAs was verified by quantitative real-time PCR (qRT-PCR). Results: A total of 2571 circRNAs with significantly different expression between the groups were identified by microarray analysis. GO, KEGG, and pathway enrichment analyses reveal that these differentially expressed circRNAs (DECs) were complicated in many biological pathways that may be related to EGFR-TKI resistance such as ABC transporter and PI3K-Akt pathways. A circRNA-microRNA network was constructed by 10 circRNAs potentially involved in EGFR-TKI resistance togethering with their corresponding microRNAs (miRNAs). Consistent with the results of microarray assay, hsa_circ_0030591 and hsa_circ_0040348 were validated to be upregulated in gefitinib-resistant patients by qRT-PCR. Conclusions: Our study provides valuable data on circRNAs expression profiles detected in liquid biopsy for LUAD patients with acquired gefitinib resistance, and we validate that upregulations of hsa_circ_0030591 and hsa_circ_0040348 may play key roles in EGFR-TKI resistance and thus serving as candidates for biomarker.

Project description:The purpose of this investigation was to evaluate the effects of aging and lifelong exercise on skeletal muscle components of the innate immune system. Additionally, the effects of an acute resistance exercise (RE) challenge were explored. Three groups of men were studied: young exercisers (YE: n = 10, 25 ± 1 yr; V̇o2max: 53 ± 3 mL/kg/min; quadriceps size: 78 ± 3 cm2), lifelong aerobic exercisers with a 53 ± 1 yr training history (LLE; n = 21, 74 ± 1 yr; V̇o2max: 34 ± 1 mL/kg/min; quadriceps size: 67 ± 2 cm2), and old healthy nonexercisers (OH: n = 10, 75 ± 1 yr; V̇o2max: 22 ± 1 mL/kg/min, quadriceps size: 56 ± 3 cm2). Vastus lateralis muscle biopsies were obtained in the basal state and 4 h after RE (3 × 10 reps, 70% of 1 repetition maximum) to assess Toll-like receptors (TLR)1-10, TLR adaptors (Myd88 and TRIF), and NF-κB pathway components (IκΒα and IKKβ) mRNA expression. Basal TLR3, TLR6, and TLR7 tended to be higher (P ≤ 0.10) with aging (LLE and OH combined). In general, RE increased expression of TLR1 and TLR8 (P ≤ 0.10) and TLR3 and TLR4 (P < 0.05), although TLR3 did not respond in OH. Both TLR adaptors also responded to the exercise bout; these were primarily (Myd88, main effect P ≤ 0.10) or exclusively (TRIF, P < 0.05) driven by the OH group. In summary, aging appears to increase basal expression of some innate immune components in human skeletal muscle, and lifelong aerobic exercise does not affect this age-related increase. An exercise challenge stimulates the expression of several TLRs, while the TLR adaptor response appears to be dysregulated with aging and maintained with lifelong exercise. Partially preserved muscle mass, coupled with a notable immunity profile, suggests lifelong exercisers are likely better prepared for a stress that challenges the immune system.NEW & NOTEWORTHY Findings from this investigation provide novel insight into the effect of aging and lifelong aerobic exercise on structural components of the innate immune system in skeletal muscle of humans. Data presented here suggest aging increases basal expression of select Toll-like receptors (TLRs), and lifelong exercise does not impact this age-related increase. Additionally, acute exercise stimulates gene expression of several TLRs, while the adaptor response is likely dysregulated with aging and maintained with lifelong exercise.

Project description:Previous studies have indicated that aerobic exercise could reduce age related decline in cognition and brain functioning. Here we investigated the effects of aerobic exercise on intrinsic brain activity. Sixty sedentary healthy males and females (64-78 years) were randomized into either an aerobic exercise group or an active control group. Both groups recieved supervised training, 3 days a week for 6 months. Multimodal brain imaging data was acquired before and after the intervention, including 10 min of resting state brain functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling (ASL). Additionally, a comprehensive battery of cognitive tasks assessing, e.g., executive function and episodic memory was administered. Both the aerobic and the control group improved in aerobic capacity (VO2-peak) over 6 months, but a significant group by time interaction confirmed that the aerobic group improved more. Contrary to our hypothesis, we did not observe any significant group by time interactions with regard to any measure of intrinsic activity. To further probe putative relationships between fitness and brain activity, we performed post hoc analyses disregarding group belongings. At baseline, VO2-peak was negativly related to BOLD-signal fluctuations (BOLDSTD) in mid temporal areas. Over 6 months, improvements in aerobic capacity were associated with decreased connectivity between left hippocampus and contralateral precentral gyrus, and positively to connectivity between right mid-temporal areas and frontal and parietal regions. Independent component analysis identified a VO2-related increase in coupling between the default mode network and left orbitofrontal cortex, as well as a decreased connectivity between the sensorimotor network and thalamus. Extensive exploratory data analyses of global efficiency, connectome wide multivariate pattern analysis (connectome-MVPA), as well as ASL, did not reveal any relationships between aerobic fitness and intrinsic brain activity. Moreover, fitness-predicted changes in functional connectivity did not relate to changes in cognition, which is likely due to absent cross-sectional or longitudinal relationships between VO2-peak and cognition. We conclude that the aerobic exercise intervention had limited influence on patterns of intrinsic brain activity, although post hoc analyses indicated that individual changes in aerobic capacity preferentially influenced mid-temporal brain areas.

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Comprehensive analysis of circular RNA profiles in skeletal muscles of aging mice and after aerobic exercise intervention.

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Comprehensive analysis of circular RNA profiles in skeletal muscles of aging mice and after aerobic exercise intervention.

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