Online Supplement to

Exercise – putting action into our epigenome

Short title: Exercise and epigenetics

Joshua Denham, Francine Z. Marques, Brendan J. O’Brien, Fadi J. Charchar

School of Health Sciences, University of Ballarat, Ballarat, VIC, Australia

Corresponding Author

Fadi Charchar, Room 228, F Building, Oppy Drive, University of Ballarat, Mt Helen, 3350. P: (03) 5327 6098, Fax: (03) 5327 9602

Email:

Electronic Supplementary Material

Table S1. Summary of relevant literature on exercise and miRNAs.

miRNA/s impacted / Cell type / Participant or animal phenotypesa,b,c,d,e / Exercisef,g,h,I,j / Reference
↑ or ↓ / Acute effects / Chronic effects / Acute and chronic effects
Human studies
↑ / •miR-125a
•miR-210
•miR-222
•miR-29a (M only)
•let-7d (F only)
•miR-21 / Serum / 50 (low VO2max) and 50 (high VO2max), 40-45, M+F, U, Low - ~102 (ml.kg0.75.min-1) high - ~148 (ml.kg0.75.min-1) / N/A / Bye et al.[1]
↓ / •miR-151 (M only)
•miR-652
↑ / Drosha
Exportin-5
Dicer
miR-133a
miR-133b
miR-181a / miR-29b / miR-1 / Myocytes / 9, 23, M, <2 hours per week, 44.1 / Acute and chronic, aerobic (cycling), Acute – 60 (at ~70% of VO2max); Chronic (4 days of 45 mins at ~75% of VO2max, 2 days of 90 min at ~75% of VO2max and 4 days of 6x5 min at ~95% of VO2max) / Russell et al. [2]
↓ / miR-9
miR-23a
miR-23b / miR-31
↑ / miR-21-5p
miR-24-2-5p
miR-27a-5p
miR-181a-5p / Leukocytes / 8, 21.7, M, athletic (National level ski athletes), 74.8 / Acute, aerobic (30 min treadmill run at 80% VO2peak) / Tonevitsky et al. [3]
↓ / miR-486 / Serum / 8, 21.5, M, SED, 41.5 / Acute and chronic, aerobic (cycling), acute – 60 min cycle at 70% of VO2max and chronic – 30 min at 70% of VO2max, 3, 4 / Aoi et al. [4]
↑ / miR-363
miR-338-3p
miR-590-5p
miR-7
miR-30e
miR-142-3p
miR-29c
miR-29b
miR-29a
miR-192
miR-142-5p / Blood natural killer cells / 13, 24, M, U, 48.2 / Acute, aerobic (cycling), 10 x 2 min efforts at ~75% of VO2max with 1 min rest between efforts) / Radom-Aizik et al. [5]
↓ / miR-126
miR-126*
let-7e
miR-130a
miR-151-5p
miR-199a-5p
miR-199a-3p
miR-221
miR-223
miR-326
miR-328
miR-652
↑ / miR-126 (cycle VO2max test, 4 hour cycle at 70% of VO2max, Marathon race only)
miR-133 (resistance training and marathon race only) / Plasma / 59, middle-aged, M+F, U, 23.6-59.8‖ / Acute, aerobic (four groups: cycle VO2max test, 4 hour cycle at 70% of VO2max, marathon race and resistance training) / Uhlemann et al. [6]
↑ / miR-20a (acute after training) / miR-146a (acute after training)
miR-222 (acute after training)
miR-21
miR-221 / Plasma / 10, 19.1, M, athletic (rowers), 52 / Acute (before and after training) and chronic, aerobic (endurance rowing), acute (cycle VO2max test) and chronic – 60-180 (20-24 strokes per minute), 90 (in total) / Baggish et al. [7]
↑ / miR-26b
miR-1225-5p
miR-338-3p
miR-181c
miR-363
miR-181a
miR-181b
miR-181a-2*
miR-132
miR-15a
miR-939
miR-7
miR-140-5p
miR-21*
miR-940 / Blood mononuclear cells / 12, 22, M, U, 42.7 / Acute, aerobic (cycling), 10 x 2 min efforts at ~75% of VO2max with 1 min rest between efforts) / Radom-Aizik et al. [8]
↓ / miR-652, let-7e
miR-99b, miR-125b
miR-125a-5p
miR-151-3p
miR-130a
miR-126
miR-199b-3p
miR-23b
miR-221
miR-199a-5p
miR-584
miR-145
miR-31
miR-486-5p
miR-151-5p
miR-320
miR-451
↓ / miR-133a (after bed rest)
miR-1 (after bed rest)
miR-23a (acute exercise after bed rest) / Myocytes / 12, 26.2, M, U, ~49 (after bed rest) / Chronic (7 days of bed rest – physical inactivity) and acute (after 7 days of bed rest), aerobic (knee extensor exercise), 45min / Ringholm et al. [9]
↑ / ••miR-451 / Myocytes / 56, 18-30, M / Chronic, resistance exercise, U, 5, 12 / Davidsen et al. [10]
↓ / ••miR-378
••miR-26a
••miR-29a
↑ / miR-125a
miR-183
miR-189
miR-432*
miR-616
miR-637
miR-575 / Myocytes / 8, 23, M, SED, 47 / Chronic, aerobic, 45 (at 70% of VO2max), 4, 6 / Keller et al. [11]
↓ / miR-26b
miR-144
miR-101
miR-455
miR-338
miR-29b
miR-28
miR-1
miR-589
miR-451
miR-98
miR-92
miR15b
miR-133
↓ / miR-1 / Myocytes / 27, ~80, M+F / Chronic, resistance exercise, U, 2, 12 / Mueller et al. [12]
↑ / miR-520d-3p
miR-1225-5p
miR-1238
miR-125a-5p
miR-145
miR-181b
miR-193a-3p
miR-197
miR-212
miR-223
miR-340*
miR-365
miR-485-3p
miR-505
miR-629*
miR-638
miR-939
miR-940 / Neutrophils / 11, 22.2, M, U, 42 / Acute, aerobic (cycling), 10 x 2 min efforts at ~75% of VO2max with 1 min rest between efforts) / Radom-Aizik et al. [13]
↓ / miR-20a miR-660
miR-106a miR-96
miR-20b
miR-17
miR-93
miR-130b
miR-16
let-7i
miR-107
miR-126
miR-130a
miR-151-5p
miR-185
miR-18a
miR-18b
miR-194
miR-22
miR-363
↑ / miR-1
miR-133a / Myocytes / 10, 30.5, RA, ~53 / Acute and chronic, aerobic (cycling), acute – 60 min cycle and chronic – 60 to 150, 5, 12 / Nielsen et al. [14]
↓ / miR-1
miR-133a
miR-133b
miR-206
↑ / pri-miR-206 (Y+O)
pri-miR-133a-2 (Y+O) / Myocytes / 12 – 6 young (Y) and 6 old (O), young – 29 and old – 70 / Acute, resistance exercise, 8 x 10 of knee extension exercise @ 70% of 1RM. / Drummond et al. [15]
↓ / miR-1 (Y)
pri-miR-1-2 (Y)
pri-miR-133a-1 (Y)
Rodent studies
↑ / miR-21
miR-144
miR-145 / Cardiac myocytes / Wistar rats, U, F / Chronic, aerobic (swimming), 60, 5, 8 / Ma et al. [16]
↓ / miR-124
↑ / miR-126 / Cardiac myocytes / Wistar rats, U, F / Chronic, aerobic (swimming), 60, 5, 10 / Da Silva Jr et al. [17]
↑ / miR-124 / Brain / Wistar rats, U, M / Chronic, aerobic (treadmill running ~40% (low intensity group) or ~75 (high intensity group) of VO2max), 30, 7, 2 / Mojtahedi et al. [18]
↑ / miR-21 / Neuronal cells (spinal cord) / Sprague-Dawley rats, U, F / Chronic, aerobic (passive cycling), 60 (@45rpm), 5, 10‡ / Liu et al. [19]
↑ / miR-126 (SHR) / Myocytes / WKY and SHR, 12-week-old, U / Chronic, aerobic (swimming), 60, 5, 10 / Fernandes et al. [20]
↓ / miR-16 (SHR+WKY)
miR-21(SHR)
↓ / miR-494 / Myocytes / C57BL/6J mice, 9-week-old, M / Chronic, aerobic (swimming), 7x15 min bouts with 5 min rests, 7 / Yamamoto et al. [21]
↑ / miR-27a
miR-27b / Cardiac myocytes / Wistar rats, U, F / Chronic, aerobic (swimming), 60, 5, 10 / Fernandes et al. [22]
↓ / miR-143
↑ / miR-29a
miR-29c / Cardiac myocytes / Wistar rats, U, F / Chronic, aerobic (swimming), 60, 5, 10 / Soci et al. [23]
↓ / miR-1
miR-133a
miR-133b
↑ / miR-21 / Neuronal cells (spinal cord) / Sprague-Dawley rats, U, F / Chronic, aerobic (passive cycling), 60 (@45rpm), 5, 10-31 day / Liu et al. [24]
↓ / miR-15b
↑ / Exercised mice miR-21
Immobilised mice
miR-680
miR-696
miR-705
miR-762 / Myocytes / C57BL/6 mice, 8-week-old, U / Chronic, aerobic (treadmill running), 20-60, 5, 4 / Aoi et al. [25]
↓ / miR-696
miR-709
miR-720
↑ / miR-7*
MM_264
miR-189
miR-377
miR-98
miR-126*
miR-148b
miR-338
miR-183
miR-489 / Myocytes / Sprague-Dawley rats, 6-months-old, M / Chronic, Hind-limb suspension (immobilisation) for 2-7 days / McCarthy et al. [26]
↓ / miR-23b
miR-27b
miR-333
miR-20a
miR-221
miR-222
miR-499
miR-505
↑ / miR-1
miR-107
miR-181 / Myocytes / C57BL/6 mice, U, M / Acute, aerobic (treadmill running), 90 / Safdar et al.[27]
↓ / miR-23
↑ / pri-miR-1-2
pri-miR-133a-2
pri-miR-206 / Myocytes / C57BL/6 mice, 10-weeks-old, M / Mechanical functional overload / McCarthy et al. [28]
↓ / miR-1
miR-133a

a = Number of subjects or breed of rodent.

b = Age of subjects (years).

c = Sex of subjects – Male (M) /female (F) or both genders (M+F)

d = Physical activity level – sedentary (SED), recreationally active (RA), athletic, unspecified (U)

e = maximal aerobic fitness (VO2max) measured in ml.kg.min-1.

f = Type of exercise intervention – acute, chronic or acute and chronic exercise or not applicable (N/A).

h = Minutes of exercise training per session.

i = Day/s or sessions of exercise per week.

j = Weeks (or months☨) of exercise training (if any).

‡ = Indicates data from individuals from which the main findings originate from.

‖ = Indicates range of average VO2max values from each of the participants in the cycle VO2max test, four hour cycle at 70% of VO2max, marathon race and resistance training group.

• = Participants with a low VO2max compared to participants with a low VO2max.

•• = Low responders compared to high responders.

Min = minutes; miR = micro-RNA; ↓ = decrease (s/d); ↑ = increase (s/d); * = passenger miRNA; pri = primary miRNA; VO2peak = peak volume of oxygen; WKY = Wistar Kyoto rats; SHR = Spontaneously hypertensive rat.

References

1.Bye A, Rosjo H, Aspenes ST, et al. Circulating microRNAs and aerobic fitness - The HUNT-Study. PLoS One 2013; 8: e57496.

2.Russell AP, Lamon S, Boon H, et al. Regulation of miRNAs in human skeletal muscle following acute endurance exercise and short term endurance training. J Physiol 2013. In press.

3.Tonevitsky AG, Maltseva DV, Abbasi A, et al. Dynamically regulated miRNA-mRNA networks revealed by exercise. BMC Physiol 2013; 13.

4.Aoi W, Ichikawa H, Mune K, et al. Muscle-enriched microRNA miR-486 decreases in circulation in response to exercise in young men. Front Physiol 2013; 4: 80.

5.Radom-Aizik S, Zaldivar FP, Haddad F, et al. Impact of brief exercise on peripheral blood NK cell gene and microRNA expression in young adults. J Appl Physiol 2013; 114: 628-36.

6.Uhlemann M, Mobius-Winkler S, Fikenzer S, et al. Circulating microRNA-126 increases after different forms of endurance exercise in healthy adults. Eur J Prev Cardiol 2012. In press.

7.Baggish AL, Hale A, Weiner RB, et al. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J Physiol 2011; 589: 3983-94.

8.Radom-Aizik S, Zaldivar F, Jr., Leu SY, et al. Effects of exercise on microRNA expression in young males peripheral blood mononuclear cells. Clin Transl Sci 2012; 5: 32-8.

9.Ringholm S, Bienso RS, Kiilerich K, et al. Bed rest reduces metabolic protein content and abolishes exercise-induced mRNA responses in human skeletal muscle. Am J Physiol Endocrinol Metab 2011; 301: E649-58.

10.Davidsen PK, Gallagher IJ, Hartman JW, et al. High responders to resistance exercise training demonstrate differential regulation of skeletal muscle microRNA expression. J Appl Physiol 2011; 110: 309-17.

11.Keller P, Vollaard NB, Gustafsson T, et al. A transcriptional map of the impact of endurance exercise training on skeletal muscle phenotype. J Appl Physiol 2011; 110: 46-59.

12.Mueller M, Breil FA, Lurman G, et al. Different molecular and structural adaptations with eccentric and conventional strength training in elderly men and women. Gerontology 2011; 57: 528-38.

13.Radom-Aizik S, Zaldivar F, Jr., Oliver S, et al. Evidence for microRNA involvement in exercise-associated neutrophil gene expression changes. J Appl Physiol 2010; 109: 252-61.

14.Nielsen S, Scheele C, Yfanti C, et al. Muscle specific microRNAs are regulated by endurance exercise in human skeletal muscle. J Physiol 2010; 588: 4029-37.

15.Drummond MJ, McCarthy JJ, Fry CS, et al. Aging differentially affects human skeletal muscle microRNA expression at rest and after an anabolic stimulus of resistance exercise and essential amino acids. Am J Physiol Endocrinol Metab 2008; 295: e1333-40.

16.Ma Z, Qi J, Meng S, et al. Swimming exercise training-induced left ventricular hypertrophy involves microRNAs and synergistic regulation of the PI3K/AKT/mTOR signaling pathway. Eur J Appl Physiol 2013.

17.D. A. Silva ND J, Fernandes T, Soci UP, et al. Swimming training in rats increases cardiac MicroRNA-126 expression and angiogenesis. Med Sci Sports Exerc 2012; 44: 1453-62.

18.Mojtahedi S, Kordi M, Soleimani M, et al. Effect of different intensities of short term aerobic exercise on expression of miR-124 in the hippocampus of adult male rats. J Res Med Sci 2012; 14: 16-20.

19.Liu G, Detloff MR, Miller KN, et al. Exercise modulates microRNAs that affect the PTEN/mTOR pathway in rats after spinal cord injury. Exp Neurol 2012; 233: 447-56.

20.Fernandes T, Magalhaes FC, Roque FR, et al. Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: role of microRNAs-16, -21, and -126. Hypertension 2012; 59: 513-20.

21.Yamamoto H, Morino K, Nishio Y, et al. MicroRNA (miRNA)-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcriptional factor A (mtTFA) and forkhead box j3 (Foxj3). Am J Physiol Endocrinol Metab 2012; 303: E1419-27.

22.Fernandes T, Hashimoto NY, Magalhaes FC, et al. Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7). Hypertension 2011; 58: 182-9.

23.Soci UP, Fernandes T, Hashimoto NY, et al. MicroRNAs 29 are involved in the improvement of ventricular compliance promoted by aerobic exercise training in rats. Physiol Genomics 2011; 43: 665-73.

24.Liu G, Keeler BE, Zhukareva V, et al. Cycling exercise affects the expression of apoptosis-associated microRNAs after spinal cord injury in rats. Experimental neurology 2010; 226: 200-6.

25.Aoi W, Naito Y, Mizushima K, et al. The microRNA miR-696 regulates PGC-1α in mouse skeletal muscle in response to physical activity. Am J Physiol Endocrinol Metab 2010; 298: e799-806.

26.McCarthy JJ, Esser KA, Peterson CA, et al. Evidence of MyomiR network regulation of beta-myosin heavy chain gene expression during skeletal muscle atrophy. Physiol Genomics 2009; 39: 219-26.

27.Safdar A, Abadi A, Akhtar M, et al. miRNA in the regulation of skeletal muscle adaptation to acute endurance exercise in C57Bl/6J male mice. PLoS One 2009; 4: e5610.

28.McCarthy JJ, Esser KA. MicroRNA-1 and microRNA-133a expression are decreased during skeletal muscle hypertrophy. J Appl Physiol 2007; 102: 306-13.