Non-Coding RNAs in the Transcriptional Network That Differentiates Skeletal Muscles of Sedentary from Long-Term Endurance- and Resistance-Trained Elderly

Abstract

In a previous study, the whole transcriptome of the vastus lateralis muscle from sedentary elderly and from age-matched athletes with an exceptional record of high-intensity, life-long exercise training was compared—the two groups representing the two extremes on a physical activity scale. Exercise training enabled the skeletal muscle to counteract age-related sarcopenia by inducing a wide range of adaptations, sustained by the expression of protein-coding genes involved in energy handling, proteostasis, cytoskeletal organization, inflammation control, and cellular senescence. Building on the previous study, we examined here the network of non-coding RNAs participating in the orchestration of gene expression and identified differentially expressed micro- and long-non-coding RNAs and some of their possible targets and roles. Unsupervised hierarchical clustering analyses of all non-coding RNAs were able to discriminate between sedentary and trained individuals, regardless of the exercise typology. Validated targets of differentially expressed miRNA were grouped by KEGG analysis, which pointed to functional areas involved in cell cycle, cytoskeletal control, longevity, and many signaling pathways, including AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), which had been shown to be pivotal in the modulation of the effects of high-intensity, life-long exercise training. The analysis of differentially expressed long-non-coding RNAs identified transcriptional networks, involving lncRNAs, miRNAs and mRNAs, affecting processes in line with the beneficial role of exercise training.

Non-Coding RNAs as Regulators of Myogenesis and Postexercise Muscle Regeneration

“…This may result in higher muscle mass and mitochondrial dynamics in skeletal muscle [141,142]. Additionally, higher expression of MALAT1 in muscles after regular exercise was described [105]. Apart from its role in myogenic differentiation, i.e., modulation of MYOD transcriptional activity, it was shown that MALAT1 influences synapse formation by regulating the expression of genes involved in synaptogenesis, e.g., NLG1 encoding NEUROLIGIN1 and CADM1 [143].…”

“…Thus far, the exact molecular mechanisms responsible for body adaptation to exercise have not been defined. However, it seems that physical activity can regulate the expression of various genes by affecting DNA methylation [99], histone modifications [100], miRNA, or lncRNA expression [101][102][103][104][105]. Analyses of material obtained from human skeletal muscle biopsies or body fluids have shown that various training protocols and body adaptations differently impact miRNA and lncRNA levels.…”

“…Changes in this lncRNA expression were related to extracellular matrix organization, sprouting angiogenesis, positive regulation of PI3K (a pathway inducing skeletal muscle hypertrophy), positive regulation of intracellular signal transduction, striated muscle contraction, and myofiber innervation [104]. GAS5, SNHG12, HOTAIRM1, ZFAS1, RP11-48O20.4 (LINC01133), HOXD-AS1 (HAGLR), SNHG12, EMX2OS, SNHG15, LINC00152 (CYTOR), SNHG1, and HOXC-AS1 [105] Analysis of 242 differently expressed lncRNAs in trained vs. sedentary elderly men allowed one to pinpoint transcriptional networks affecting processes connected with the beneficial effect of exercise training [105]. Thus, lncRNA GAS5 was significantly downregulated in trained men and was linked to anti-inflammatory effect and increase in muscle mass and strength.…”

Non-coding RNA basis of muscle atrophy

“… 121 In a further study, differentially expressed ncRNAs and miRNAs in muscle atrophy were induced by long-term inactivity mainly involved in cell-cycle regulation, cytoskeleton control, and an AMP-activated protein kinase (AMPK) pathway. 122 …”

Editorial for the Special Issue “Molecular Bases of Senescence”

“…Exercise has enabled skeletal muscle to counteract age-related sarcopenia by inducing a wide range of adaptations, supported by the expression of genes encoding proteins involved in energy management, proteostasis, cytoskeletal organisation, control of inflammation and cellular senescence. De Sanctis et al [10] had previously examined the entire transcriptome of the vastus lateralis muscle of sedentary elderly and similarly aged athletes with an exceptional record of high-intensity, lifelong training. In this paper, the authors describe the network of differentially expressed non-coding RNAs in the two classes and some of their possible targets and roles (Figure 2).…”