RNA-Sequencing Muscle Plasticity to Resistance Exercise Training and Disuse in Youth and Older Age
Abstract
:1. Introduction
2. Transcriptional Responses to RET
Reference | Population | Study Design | Transcriptomic Responses | Phenotypic Adaptations |
---|---|---|---|---|
RET | ||||
Robinson et al. [11] | Young adults (n = 11, 5 M/6 F, 23.7 ± 3.5 yr). Older adults (70.3 ± 3.9 yr, n = 9, 5 M/4 F). | 12 weeks RET. (another group: 12 weeks high intensity interval training) (another group: 12 weeks combined aerobic and resistance exercise). | Regulation of mitochondrial, muscle growth and insulin-related genes (albeit to a lesser extent than high intensity interval training). Upregulation of genes pertaining to angiogenesis and regulation of angiogenesis. | Significant improvements in fat free mass, muscle strength and insulin sensitivity in both age groups. No change in mitochondrial respiration in either age group. |
Lim et al. [33] | Young males (n = 21, 23.7 ± 2.5 yr). | 10 weeks RET. | Up-regulation in genes related to muscle development, stress response, metabolism, tran-scription factor and cell death (albiet to a lesser extent than acute RE). | Increase in muscle strength and fibre cross-sectional area [34]. |
Chapman et al. [35] | RET-trained males (n = 7, 42.1 ± 5.8 yr). Age-matched untrained females (n = 8) and males (n = 7). | +15 yr RET experience | Upregulation in genes related to cellular respiration pathways compared to untrained controls. Downregulation in pathways associated with the negative regulation of cell proliferation compared untrained controls. | Greater muscle fibre cross sectional area in RET trained adults (vs. untrained controls). |
Kulkarni et al. [36] | Older males and females with placebo (n = 48, ≥65 yr). Older males and females with metformin (n = 46, ≥65 yr). | 14 weeks RET. | Increased expression of genes related to extracellular matrix remodelling pathways (compared to baseline). Downregulation in genes related to RNA processing pathways (compared to baseline). | Increased lean body mass, thigh muscle mass and muscle strength [37]. |
Lavin et al. [38] | Older adults (n = 31, 18 F/13 M, 70 ± 4 yr) | 14 weeks RET. | Two modules of genes significantly and positively related to the change in mid-thigh muscle cross-sectional area, of which the hubs were related to immune and inflammatory processes, specifically: defence response to virus, regulation of leukocyte activation, positive regulation of defence response, positive regulation of cytokine production, and negative regulation of immune system processes (part of “prediction analysis”). | Decreased percentage body fat, increased mid-thigh muscle cross-sectional area and thigh muscle mass. |
Bolotta et al. [39] | Life-long exercise trained older adults (n = 9, 65–80 yr). Sedentary older adults (n = 5, 70–76 yr). | Life-long RET (n = 4) or aerobically exercise trained (n = 5). | Upregulation in genes related to insulin signalling, energy production (e.g., TCA cycle), mTOR signalling, mitochondria, calcium-regulated energy processes and the cytoskeleton/focal adhesions (compared to sedentary controls). | Fast type fibres were larger in RET versus aerobically trained adults. |
Disuse | ||||
Willis et al. [40] | Healthy young (22 yr) males (n = 8). | Four-day unilateral lower limb immobilisation. | Downregulation of mitochondrial and myogenesis. Upregulation of ribosome biogenesis, UPS catabolism, and ribonucleoprotein complex organization/mRNA processing. | Decreased muscle mass (−1.7%) and MPS (−16.2%), with high inter-individual variability. Associations between gene networks phenotypic changes. |
Sarto et al. [41] | Active young (22 yr) male adults (n = 12). Focus on NMJ. | Ten-day unilateral lower limb suspension (ULLS) followed by a 21-day readaptation program. | Upregulation of ACh receptor subunits genes. Downregulation of Homer proteins genes. Changes in expression of other genes (e.g., neuregulings, neurotrophins, ErbBs, Wnts) indicative of NMJ molecular instability. Downregulation of ion channels gene set. Most ULLS-induced transcrioptional changes were restored after the readapatation program. | Deacreased muscle volume (−4.5%). NMJ transmission stability was unchanged after ULLS. Increased motor unit potential complexity and decreased motor unit firing rates after ULLS. Most ULLS-induced phenotypic changes were restored after the readapatation program. |
McFarland et al. [42] | Healthy men (n = 22) and women (n = 3) (20–54 yrs) randomized in two groups. | Five-week −6° head down tilt bed rest. Two parallel groups: bed rest only (n = 9) and bed rest with exercise (n = 16). | Downregulation of virtually all aspects of mitochondrial activity. Upregulation of ligands with a key role in pain. The exercise countermeasure normalized most of the genes related to mitochondrial activity. | Reported in other manuscript [43]. Decreased muscle volume (quadriceps; −9%). Exercise during bed rest reduced the muscle atrophy (quadriceps; −5%) |
Mahmassani et al. [44] | Healthy older and younger male (n = 13) and female (n = 13) adults (mean age; ~52 yrs). | Five-day bed rest. Participants were categorized into high or low susceptibility for insuling resistance after bed rest. | Gene ontologies (GO) that changed in both high and low susceptibility groups: muscle contraction, muscle filament sliding, mitonchondrial ATP synthesis. GOs altered only in high-susceptibility group: lipid metabolic processes, lipid storage, protein homotetramerization. | Both high and low susceptibility groups become insulin-resistant after bed rest but the “High” group had 49% lower insulin sensitivity after bed rest, versus 15% in the “Low” group. |
Mahmassani et al. [45] | Healthy young (23 yr; n = 9) and older (68 yr, n = 18) participants (13 men and 14 women). | Five-day bed rest. | Common pathways altered in both young and older: Acting cytoskeleton signaling, ILK and RhoA signaling, Mitochondrial dysfunction and calcium signaling. Increased inflammation and fibrotic gene expression in older group only. 51 genes changed in young but not older; after bed rest, the expression of these genes in young nearly matched that in older participants. | Leg lean mass decreased 3.4% in the older group, but did not change in the young group (similar results for total lean mass and myofiber CSA). Leg strength decreased after bed rest in both groups. |
Standley et al. [46] | Healthy older (between 60–79 yrs) men (n = 11) and women (n = 10). | Ten-day bed rest. Two groups; bed rest only (n = 9), and bed rest with nutritional supplementation (n = 12). | Downregulation of genes related to mitochondria, ribosomes, and oxidative metabolism. Upregulation of genes involved in extracellular matrix, focal adhesion, and collagen. The nutritional supplementation offset some of these changes. | CSA of type IIa fibers decreased in the bed rest group. |
Mahmassani et al. [47] | Healthy older adults (~72 yrs; n = 8, 6 females and 2 males). | Two-week reduced activity period (from 11,000 steps/day to 2200 steps/day). RNA-seq of muscle and ribosomal profiling. | Altered response for several transcripts (e.g., PFKFB3, GADD45A, NMRK2) in response to leucine stimulation. Uncoupled translation for mTORC1 pathway. Reduction in genes related with ribosomal proteins and alteration of circadian regulators | Unchanged leg lean mass. Tendency for reduced Type I fiber size. Glucose tolerance and insulin sensitivity did not change. |
3. Transcriptional Responses to Disuse
4. Analytical Considerations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Tool | Highlighted Use | Reference |
---|---|---|
FastQC | Quality check of raw sequence reads | [92] |
Cutadapt | Trimming and/or filtering of raw sequence reads | [93] |
SOAPnuke | [94] | |
Trimmomatic | [95] | |
Histat2 | Splice-aware genome alignment | [96] |
STAR | [97] | |
TopHat2 | [98] | |
featureCounts | Genomic feature counting of aligned reads | [99] |
htseq-count | [100] | |
Kallisto | Pseudoalignment and quantification of transcript abundance | [101] |
Sailfish | [102] | |
Salmon | [103] | |
tximport | Infer gene counts from transcript-level estimates | [104] |
DESeq2 | Differential gene expression analysis | [105] |
EdgeR | [106] | |
Limma | [107] | |
IPA | Facilitates (among other things) knowledge-based network inference | [71] |
NetworkAnalyst | [73] | |
STRING | [72] | |
WGCNA | Facilitates data-driven network analysis | [108] |
clusterProfiler | Overrepresentation analysis and/or gene set enrichment analysis | [81] |
DAVID | [82] | |
Enrichr | [85] | |
g:Profiler | [86] | |
Broad Institute GSEA software | [84] | |
WebGestalt | [83] |
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Fernandez-Gonzalo, R.; Willis, C.R.G.; Etheridge, T.; Deane, C.S. RNA-Sequencing Muscle Plasticity to Resistance Exercise Training and Disuse in Youth and Older Age. Physiologia 2022, 2, 164-179. https://doi.org/10.3390/physiologia2040014
Fernandez-Gonzalo R, Willis CRG, Etheridge T, Deane CS. RNA-Sequencing Muscle Plasticity to Resistance Exercise Training and Disuse in Youth and Older Age. Physiologia. 2022; 2(4):164-179. https://doi.org/10.3390/physiologia2040014
Chicago/Turabian StyleFernandez-Gonzalo, Rodrigo, Craig R. G. Willis, Timothy Etheridge, and Colleen S. Deane. 2022. "RNA-Sequencing Muscle Plasticity to Resistance Exercise Training and Disuse in Youth and Older Age" Physiologia 2, no. 4: 164-179. https://doi.org/10.3390/physiologia2040014