Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: brief report

Abstract

Exercise improves cardiometabolic and vascular function, although the mechanisms remain unclear. Our objective was to demonstrate the diversity of circulating extracellular RNA (ex-RNA) release during acute exercise in humans and its relevance to exercise-mediated benefits on vascular inflammation. We performed plasma small RNA sequencing in 26 individuals undergoing symptom-limited maximal treadmill exercise, with replication of our top candidate miRNA in a separate cohort of 59 individuals undergoing bicycle ergometry. We found changes in miRNAs and other ex-RNAs with exercise (e.g., Y RNAs and tRNAs) implicated in cardiovascular disease. In two independent cohorts of acute maximal exercise, we identified miR-181b-5p as a key ex-RNA increased in plasma after exercise, with validation in a separate cohort. In a mouse model of acute exercise, we found significant increases in miR-181b-5p expression in skeletal muscle after acute exercise in young (but not older) mice. Previous work revealed a strong role for miR-181b-5p in vascular inflammation in obesity, insulin resistance, sepsis, and cardiovascular disease. We conclude that circulating ex-RNAs were altered in plasma after acute exercise target pathways involved in inflammation, including miR-181b-5p. Further investigation into the role of known (e.g., miRNA) and novel (e.g., Y RNAs) RNAs is warranted to uncover new mechanisms of vascular inflammation on exercise-mediated benefits on health. How exercise provides benefits to cardiometabolic health remains unclear. We performed RNA sequencing in plasma during exercise to identify the landscape of small noncoding circulating transcriptional changes. Our results suggest a link between inflammation and exercise, providing rich data on circulating noncoding RNAs for future studies by the scientific community.

Small non-coding RNAs are altered by short-term sprint interval training in men

“…Consistent with the effects of acute exercise (Shah et al. ), chronic exercise training resulted in marked changes to circulating small ncRNA abundance in a diverse RNA species.…”

“…Others that were decreased after short‐term SIT in our study were increased in plasma samples from individuals after acute maximal aerobic exercise (miR‐185‐5p, miR‐769‐5p and miR‐423‐3p) (Shah et al. ). Two of the three miRNAs (miR‐185‐5p and miR‐423‐3p) targeted pathways such as viral carcinogenesis, cell cycle, p53 signaling, and microRNAs in cancer.…”

“…Whether other small ncRNAs are vital for controlling exercise adaptations is relatively unknown. Recently, the acute exercise-induced changes to small ncRNAs in plasma were revealed (Shah et al 2017). As the acute effects of exercise are typically proinflammatory and required for adaptation, the many health benefits gained from regular exercise occur over long-term with training.…”

“…Consistent with the effects of 1.32 0.02 0.03 tRNA-Lys-CTT-4-1 1.30 0.01 0.02 tRNA-Gly-CCC-7-1 1.29 0.002 0.01 tRNA-Lys-CTT-1-1 1.24 0.01 0.02 tRNA-Lys-CTT-1-2 1.24 0.0108356 0.02 tRF-1_tRNA-Val-CAC-1-2 1.24 0.0006 0.01 tRF-1_tRNA-Asp-GTC-1-1 1.22 0.0025 0.01 GENSCAN00000025626 1.13 0.02 0.04 tRNA-Lys-TTT-5-1 1.11 0.004 0.01 tRNA-Lys-TTT-3-1 1.10 0.00 0.01 tRNA-Lys-TTT-3-2 1.10 0.004 0.01 tRNA-Lys-TTT-3-3 1.10 0.004 0.01 tRNA-Lys-TTT-3-4 1.10 0.004 0.01 tRNA-Lys-TTT-3-5 1.10 0.004 0.01 tRNA-leader_[6]_tRNA-His-GTG-1-5 1.06 0.0095 0.02 tRF-1_tRNA-Arg-CCT-3-1 1.04 0.02 0.04 tRF-1_tRNA-Thr-CGT-2-1 1.04 0.001 0.01 tRF-1_tRNA-Thr-TGT-4-1 1.01 0.03 0.04 tRNA-Glu-TTC-6-1 1.00 0.002 0.01 tRF-1_[6]_tRNA-Phe-GAA-1-4 0.98 0.0008 0.01 GENSCAN00000007596 0.95 0.0008 0.01 SNORD31B-ENSG00000201847.1 0.94 0.005 0.01 GENSCAN00000017537 0.94 0.002 0.01 GENSCAN00000003559 0.92 0.02 0.04 AC124068.2-ENSG00000261441.1 0.92 0.02 0.035 GENSCAN00000045642 0.90 0.009 0.02 TEX41-(59) 0.90 0.02 0.04 tRNA-leader_tRNA-His-GTG-1-5 0.87 0.003 0.01 GENSCAN00000037392 0.86 0.004 0.01 GENSCAN00000012181 0.86 0.005 0.01 GENSCAN00000033127 0.85 0.006 0.01 tRNA-Ala-AGC-19-1 0.85 0.002 0.01 tRNA-Ala-AGC-21-1 0.85 0.002 0.01 GENSCAN00000040198 0.83 0.02 0.035 GENSCAN00000035617 0.82 0.01 0.02 RNU2-37P-ENSG00000222627.1 À0.81 0.008 0.015 tRNA-Val-AAC-1-1 À0.87 0.009 0.02 tRNA-Val-AAC-1-2 À0.87 0.009 0.02 tRNA-Val-AAC-1-3 À0.87 0.009 0.02 tRNA-Val-AAC-1-4 À0.87 0.009 0.02 tRNA-Val-AAC-1-5 À0.87 0.009 0.02 tRNA-Val-AAC-3-1 À0.87 0.009 0.02 tRNA-Val-AAC-4-1 À0.87 0.009 0.02 Small non-coding RNA (ID) Log FC P-value q-value SNORD23-ENSG00000221803.1 À0.88 0.006 0.01 tRNA-Val-AAC-6-1 À0.89 0.0007 0.01 tRNA-Ala-AGC-2-1 À0.89 0.00075 0.01 tRNA-Ala-AGC-2-2 À0.89 0.00075 0.01 tRNA-Ala-AGC-3-1 À0.90 0.00075 0.01 SNHG20-(5) À0.90 0.005 0.01 tRNA-Ala-CGC-4-1 À0.90 0.0008 0.01 tRNA-Val-CAC-2-1 À0.91 0.002 0.01 SCARNA16-ENSG00000275143.1 À0.91 0.005 0.01 tRNA-Ala-AGC-7-1 À0.91 0.0007 0.01 tRNA-Ala-AGC-5-1 À0.92 0.0007 0.01 RNY3-ENSG00000202354. acute exercise (Shah et al 2017), chronic exercise training resulted in marked changes to circulating small ncRNA abundance in a diverse RNA species. Although only 13 miRNAs were regulated by SIT after applying an FDR (q < 0.05), many ncRNAs were differentially expressed (n = 1266, q < 0.05).…”

“…Recently, the acute exercise‐induced changes to small RNA molecules isolated from human plasma were revealed (Shah et al. ). Our study aimed to extend previous findings by: (1) characterizing the circulating small RNA changes to an effective form of short‐term, vigorous exercise training – sprint interval training (SIT) – and measuring them in context with the improvement to cardiorespiratory fitness and cycling performance; (2) determining the effect of short‐term SIT on the circulating miRNome; and (3) establishing whether miRNAs differentially regulated by chronic SIT were modulated by a single session of SIT.…”