Acute Exercise Leads to Regulation of Telomere-Associated Genes and MicroRNA Expression in Immune Cells

Abstract

Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health.

The influence of physical exercise and sports on telomere length - A model for telomere length and telomerase activity regulation based on a comparative assessment of literature

“…As to evidence in support of exercise related telomerase activity, a recent study found significantly raised hTERT mRNA levels in WBCs 60' after 30' of exercise at 80% of VO 2max and also tendentially raised hTERT mRNA levels in distinct T lymphocyte subpopulations (Chilton et al, 2014). The same study also screened 1,300 miRNAs levels for changes.…”

“…As to investigations of leukocytes, which include lymphocytes, it must be taken into account that lymphocytes comprise various subsets, and that relative and absolute cell counts in a blood sample might change as response to exercise (Chilton et al, 2014). Additionally, changes of telomerase activity due to exercise may be confounded by lymphocyte activation and telomerase expression due to antigen contact (Weng, 2001).…”

“…Over-630 all, and despite these apparent contradictory effects of SIRT6 on TL regulation, a loss of SIRT6 leads to telomere sequence loss (Kugel and Mostoslavsky, 2014)). Having this in mind, it is noteworthy that SIRT6 mRNA levels were increased after exercise in unsorted human WBCs but not in sorted T lymphocyte subpopulations (Chilton et al, 2014). Likewise, SIRT6 mRNA and protein is significantly higher in skeletal muscle of elite athletes than in moderately active individuals (Lindholm et al, 2014).…”

“…Most prominently, the splice variant TERTα is proposed to act as dominant negative inhibitor (Cifuentes-Rojas and Shippen, 2012;Colgin et al, 2000;Yi et al, 2000). Furthermore, a possible role of miRNAs in post-transcriptional TERT regulation was discussed recently in (Chilton et al, 2014). 130…”

“…Despite physical activity (PA) in general is seen as some sort of a "magic bullet" for the prevention and/or cure of most civilization diseases, at least strenuous physical exercise is known to trigger all three of the known telomere shortening mechanisms: (a) increased damage in skeletal muscle cells and thus increased stem cell proliferation for repair (Karalaki et al, 2009;Natale et al, 2003;Rae et al, 2010), (b) increased ROS levels due to accelerated metabo-35 lism (Radak et al, 2013), and (c) release of inflammatory mediators (Natale et al, 2003). On the other hand, studies also exist that physical exercise may act to enhance (a) telomerase activity (Chilton et al, 2014;Werner et al, 2009), (b) anti-oxidative-enzyme activity (Urso and Clarkson, 2003), and (c) anti-inflammatory functions (Peake et al, 2005). The overall effect of physical activity on TL has also been reviewed by (Kadi and Ponsot, 2010;Ludlow et al, 2013).…”