Letter Article

Exercise-Induced MicroRNA Regulation in the Mice Nervous System is Maintained After Activity Cessation

Author(s): Andrea Carvalho, Sonia Zanon and Guilherme Lucas*

Volume 10 , Issue 2 , 2021

Published on: 25 April, 2021

Page: [82 - 90] Pages: 9

DOI: 10.2174/2211536610666210426101437

Price: $65


Background: Physical exercise can improve synaptic function and protect the nervous system against many diseases by altering gene regulation. MicroRNAs (miRs) have emerged as vital regulators of gene expression and protein synthesis not only in the muscular system, but also in the brain.

Objective: Here we investigated whether exercise-induced miRs expression in the nervous and muscular systems is activity-dependent or it remains regulated even after exercise cessation.

Methods: The expression profile of miR-1, -16, and -206 was monitored by RT-PCR in the dorsal root ganglion, in the spinal cord dorsal and ventral horn, and in the soleus muscle of mice after 5 weeks of swimming training and after swimming exercise followed by 4 weeks of sedentary conditions. Control animals consisted of mice that swan daily for 30s during the 5-weeks training period, returning to the non-swimming activity for additional 4 weeks.

Results: After exercise, miR-1 was upregulated in all tissues investigated. However, the upregulation of miR-1 continued significantly high in both aspects of the spinal cord and in the soleus muscle. The expression profiles of miR-16, and -206 were increased only in the nervous system. However, miR-16 upregulation persisted in the DRG and in the spinal cord after exercise interruption, whereas miR-206 continued upregulated only in the spinal cord ventral horn.

Conclusion: Exercise training can cause long-lasting changes in the expression of miRs independently of exercise maintenance. Spatial and temporal expression of miRs is to some extent dependent on this activity. The data raised a new conceptual hypothesis on the biogenesis of miRs, indicating that long-lasting and systematic exercise can potentially cause irreversible miR regulation after activity cessation.

Keywords: MicroRNA, exercise, physical training, nervous system, skeletal muscle, spinal cord, dorsal root ganglion.

Graphical Abstract
Barker K, Eickmeyer S. Therapeutic exercise. Med Clin North Am 2020; 104(2): 189-98.
[http://dx.doi.org/10.1016/j.mcna.2019.10.003] [PMID: 32035563]
Di Liegro CM, Schiera G, Proia P, Di Liegro I. Physical activity and brain health. Genes (Basel) 2019; 10(9): E720.
[http://dx.doi.org/10.3390/genes10090720] [PMID: 31533339]
Vecchio LM, Meng Y, Xhima K, Lipsman N, Hamani C, Aubert I. The neuroprotective effects of exercise: Maintaining a healthy brain throughout aging. Brain Plast 2018; 4(1): 17-52.
[http://dx.doi.org/10.3233/BPL-180069] [PMID: 30564545]
Almeida C, DeMaman A, Kusuda R, et al. Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain. Pain 2015; 156(3): 504-13.
[http://dx.doi.org/10.1097/01.j.pain.0000460339.23976.12] [PMID: 25687543]
Zhang L, So KF. Exercise, spinogenesis and cognitive functions. Int Rev Neurobiol 2019; 147: 323-60.
Bettio L, Thacker JS, Hutton C, Christie BR. Modulation of synaptic plasticity by exercise. Int Rev Neurobiol 2019; 147: 295-322.
Mee-Inta O, Zhao ZW, Kuo YM. Physical exercise Inhibits inflammation and microglial activation. Cells 2019; 8(7): E691.
[http://dx.doi.org/10.3390/cells8070691] [PMID: 31324021]
Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75(5): 843-54.
[http://dx.doi.org/10.1016/0092-8674(93)90529-Y] [PMID: 8252621]
Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function (Reprinted from Cell, vol 116, pg 281-297, 2004). Cell 2007; 131(4): 11-29.
Hamilton AJ, Baulcombe DC. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 1999; 286(5441): 950-2.
[http://dx.doi.org/10.1126/science.286.5441.950] [PMID: 10542148]
Reinhart BJ, Slack FJ, Basson M, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000; 403(6772): 901-6.
[http://dx.doi.org/10.1038/35002607] [PMID: 10706289]
Kusuda R, Cadetti F, Ravanelli MI, et al. Differential expression of microRNAs in mouse pain models. Mol Pain 2011; 7: 17.
[http://dx.doi.org/10.1186/1744-8069-7-17] [PMID: 21385380]
Altana V, Geretto M, Pulliero A. MicroRNAs and physical activity. MicroRNA 2015; 4(2): 74-85.
[http://dx.doi.org/10.2174/2211536604666150813152450] [PMID: 26268469]
Zhao Y, Ma Z. Swimming training affects apoptosis-related microRNAs and reduces cardiac apoptosis in mice. Gen Physiol Biophys 2016; 35(4): 443-50.
[http://dx.doi.org/10.4149/gpb_2016012] [PMID: 27608614]
Horak M, Zlamal F, Iliev R, et al. Exercise-induced circulating microRNA changes in athletes in various training scenarios. PloS One 2018; 13(1): 0191060.
Güller I, Russell AP. MicroRNAs in skeletal muscle: Their role and regulation in development, disease and function. J Physiol 2010; 588(21): 4075-87.
[http://dx.doi.org/10.1113/jphysiol.2010.194175] [PMID: 20724363]
Endo K, Weng H, Naito Y, et al. Classification of various muscular tissues using miRNA profiling. Biomed Res 2013; 34(6): 289-99.
[http://dx.doi.org/10.2220/biomedres.34.289] [PMID: 24389405]
Fernandes. J, Vieira. AS, Kramer-Soares. JC, et al. Hippocampal microRNA-mRNA regulatory network is affected by physical exercise. Biochim Biophys Acta Gen Sub 2018; 1862(8): 1711-20.
Chodari L, Dariushnejad H, Ghorbanzadeh V. Voluntary wheel running and testosterone replacement increases heart angiogenesis through miR-132 in castrated diabetic rats. Physiol Int 2019; 106(1): 48-58.
[http://dx.doi.org/10.1556/2060.106.2019.06] [PMID: 30907089]
Galimov A, Merry TL, Luca E, et al. MicroRNA-29a in adult muscle stem cells controls skeletal muscle regeneration during injury and exercise downstream of fibroblast growth factor-2. Stem Cells 2016; 34(3): 768-80.
[http://dx.doi.org/10.1002/stem.2281] [PMID: 26731484]
Xia SF, Jiang YY, Qiu YY, Huang W, Wang J. Role of diets and exercise in ameliorating obesity-related hepatic steatosis: Insights at the microRNA-dependent thyroid hormone synthesis and action. Life Sci 2020; 242: 117182.
[http://dx.doi.org/10.1016/j.lfs.2019.117182] [PMID: 31863770]
Aoi W. Frontier impact of microRNAs in skeletal muscle research: A future perspective. Front Physiol 2015; 5: 495.
[http://dx.doi.org/10.3389/fphys.2014.00495] [PMID: 25601837]
Kirby TJ, McCarthy JJ. MicroRNAs in skeletal muscle biology and exercise adaptation. Free Radic Biol Med 2013; 64: 95-105.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.07.004] [PMID: 23872025]
Silva GJJ, Bye A, El Azzouzi H, Wisløff U. MicroRNAs as important regulators of exercise adaptation. Prog Cardiovasc Dis 2017; 60(1): 130-51.
[http://dx.doi.org/10.1016/j.pcad.2017.06.003] [PMID: 28666746]
Kiltschewskij D, Cairns MJ. Temporospatial guidance of activity-dependent gene expression by microRNA: Mechanisms and functional implications for neural plasticity. Nucleic Acids Res 2019; 47(2): 533-45.
[http://dx.doi.org/10.1093/nar/gky1235] [PMID: 30535081]
Solomon MG, Griffin WC, Lopez MF, Becker HC. Brain regional and temporal changes in BDNF mRNA and microRNA-206 expression in mice exposed to repeated cycles of chronic intermittent ethanol and forced swim stress. Neuroscience 2019; 406: 617-25.
[http://dx.doi.org/10.1016/j.neuroscience.2019.02.012] [PMID: 30790666]
Lin Q, Ponnusamy R, Widagdo J, et al. MicroRNA-mediated disruption of dendritogenesis during a critical period of development influences cognitive capacity later in life. Proc Natl Acad Sci USA 2017; 114(34): 9188-93.
[http://dx.doi.org/10.1073/pnas.1706069114] [PMID: 28790189]
Pan WL, Chopp M, Fan B, et al. Ablation of the microRNA-17-92 cluster in neural stem cells diminishes adult hippocampal neurogenesis and cognitive function. FASEB J 2019; 33(4): 5257-67.
[http://dx.doi.org/10.1096/fj.201801019R] [PMID: 30668139]
Fernández-Sanjurjo. M, Gonzalo-Calvo. Dd, Fernández-García. B, et al. Circulating microRNA as emerging biomarkers of exercise. Exerc Sport Sci Rev 2018; 46(3): 160-71.
Shao QY, You F, Zhang YH, et al. CSF miR-16 expression and its association with miR-16 and serotonin transporter in the raphe of a rat model of depression. J Affect Disord 2018; 238: 609-14.
[http://dx.doi.org/10.1016/j.jad.2018.06.034] [PMID: 29957478]
Xu L, Zheng YL, Yin X, et al. Excessive treadmill training enhances brain-specific microRNA-34a in the mouse hippocampus. Front Mol Neurosci 2020; 13: 7.
[http://dx.doi.org/10.3389/fnmol.2020.00007] [PMID: 32082120]
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Δ Δ C(T)) method. Methods 2001; 25(4): 402-8.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
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.
[http://dx.doi.org/10.3389/fphys.2013.00080] [PMID: 23596423]
Piscopo P, Lacorte E, Feligioni M, et al. MicroRNAs and mild cognitive impairment: A systematic review. Ageing Res Rev 2019; 50: 131-41.
[http://dx.doi.org/10.1016/j.arr.2018.11.005] [PMID: 30472218]
Safdar A, Abadi A, Akhtar M, Hettinga BP, Tarnopolsky MA. miRNA in the regulation of skeletal muscle adaptation to acute endurance exercise in C57Bl/6J male mice. PloS One 2009; 4(5): 5610.
Bastian I, Tam Tam S, Zhou XF, et al. Differential expression of microRNA-1 in dorsal root ganglion neurons. Histochem Cell Biol 2011; 135(1): 37-45.
[http://dx.doi.org/10.1007/s00418-010-0772-0] [PMID: 21170745]
Brandenburger T, Grievink H, Heinen N, et al. Effects of remote ischemic preconditioning and myocardial ischemia on microRNA-1 expression in the rat heart in vivo. Shock 2014; 42(3): 234-8.
[http://dx.doi.org/10.1097/SHK.0000000000000201] [PMID: 24978894]
Varendi K, Kumar A, Härma MA, Andressoo JO. MiR-1, miR-10b, miR-155, and miR-191 are novel regulators of BDNF. Cell Mol Life Sci 2014; 71(22): 4443-56.
[http://dx.doi.org/10.1007/s00018-014-1628-x] [PMID: 24804980]
Pan Z, Sun X, Ren J, et al. MiR-1 exacerbates cardiac ischemia-reperfusion injury in mouse models. PLoS One 2012; 7(11): e50515.
[http://dx.doi.org/10.1371/journal.pone.0050515] [PMID: 23226300]
Shan ZX, Lin QX, Deng CY, et al. MiR-1/miR-206 regulate Hsp60 expression contributing to glucose-mediated apoptosis in cardiomyocytes. FEBS Lett 2010; 584(16): 3592-600.
[http://dx.doi.org/10.1016/j.febslet.2010.07.027] [PMID: 20655308]
Yang B, Lin H, Xiao J, et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med 2007; 13(4): 486-91.
[http://dx.doi.org/10.1038/nm1569] [PMID: 17401374]
Neumann E, Brandenburger T, Santana-Varela S, et al. MicroRNA-1-associated effects of neuron-specific brain-derived neurotrophic factor gene deletion in dorsal root ganglia. Mol Cell Neurosci 2016; 75: 36-43.
[http://dx.doi.org/10.1016/j.mcn.2016.06.003] [PMID: 27346077]
Macias M, Nowicka D, Czupryn A, et al. Exercise-induced motor improvement after complete spinal cord transection and its relation to expression of brain-derived neurotrophic factor and presynaptic markers. BMC Neurosci 2009; 10: 144.
[http://dx.doi.org/10.1186/1471-2202-10-144] [PMID: 19961582]
Jung SY, Seo TB, Kim DY. Treadmill exercise facilitates recovery of locomotor function through axonal regeneration following spinal cord injury in rats. J Exerc Rehabil 2016; 12(4): 284-92.
[http://dx.doi.org/10.12965/jer.1632698.349] [PMID: 27656624]
Aqeilan RI, Calin GA, Croce CM. MiR-15a and miR-16-1 in cancer: Discovery, function and future perspectives. Cell Death Differ 2010; 17(2): 215-20.
[http://dx.doi.org/10.1038/cdd.2009.69] [PMID: 19498445]
Yamamoto H, Morino K, Nishio Y, et al. MicroRNA-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcription factor A and Forkhead box j3. Am J Physiol Endocrinol Metab 2012; 303(12): E1419-27.
[http://dx.doi.org/10.1152/ajpendo.00097.2012] [PMID: 23047984]
Zhong Z, Yuan K, Tong X, et al. MiR-16 attenuates β-amyloid-induced neurotoxicity through targeting β-site amyloid precursor protein-cleaving enzyme 1 in an Alzheimer’s disease cell model. Neuroreport 2018; 29(16): 1365-72.
[http://dx.doi.org/10.1097/WNR.0000000000001118] [PMID: 30142113]
Burak K, Lamoureux L, Boese A, et al. MicroRNA-16 targets mRNA involved in neurite extension and branching in hippocampal neurons during presymptomatic prion disease. Neurobiol Dis 2018; 112: 1-13.
[http://dx.doi.org/10.1016/j.nbd.2017.12.011] [PMID: 29277556]
Gómez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol 2002; 88(5): 2187-95.
[http://dx.doi.org/10.1152/jn.00152.2002] [PMID: 12424260]
Rao PK, Kumar RM, Farkhondeh M, Baskerville S, Lodish HF. Myogenic factors that regulate expression of muscle-specific microRNAs. Proc Natl Acad Sci USA 2006; 103(23): 8721-6.
[http://dx.doi.org/10.1073/pnas.0602831103] [PMID: 16731620]
Williams AH, Valdez G, Moresi V, et al. MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 2009; 326(5959): 1549-54.
[http://dx.doi.org/10.1126/science.1181046] [PMID: 20007902]
Ma G, Wang Y, Li Y, et al. MiR-206, a key modulator of skeletal muscle development and disease. Int J Biol Sci 2015; 11(3): 345-52.
[http://dx.doi.org/10.7150/ijbs.10921] [PMID: 25678853]
McCarthy JJ. MicroRNA-206: The skeletal muscle-specific myomiR. Biochim Biophys Acta 2008; 1779(11): 682-91.
[http://dx.doi.org/10.1016/j.bbagrm.2008.03.001] [PMID: 18381085]
Mizuno H, Nakamura A, Aoki Y, et al. Identification of muscle-specific microRNAs in serum of muscular dystrophy animal models: Promising novel blood-based markers for muscular dystrophy. PLoS One 2011; 6(3): e18388.
[http://dx.doi.org/10.1371/journal.pone.0018388] [PMID: 21479190]
Nielsen S, Scheele C, Yfanti C, et al. Muscle specific microRNAs are regulated by endurance exercise in human skeletal muscle. J Physiol 2010; 588(20): 4029-37.
[http://dx.doi.org/10.1113/jphysiol.2010.189860] [PMID: 20724368]
Olsen L, Klausen M, Helboe L, Nielsen FC, Werge T. MicroRNAs show mutually exclusive expression patterns in the brain of adult male rats. PLoS One 2009; 4(10): e7225.
[http://dx.doi.org/10.1371/journal.pone.0007225] [PMID: 19806225]
Lee ST, Chu K, Jung KH, et al. miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model. Ann Neurol 2012; 72(2): 269-77.
[http://dx.doi.org/10.1002/ana.23588] [PMID: 22926857]
Tapocik JD, Barbier E, Flanigan M, et al. microRNA-206 in rat medial prefrontal cortex regulates BDNF expression and alcohol drinking. J Neurosci 2014; 34(13): 4581-8.
[http://dx.doi.org/10.1523/JNEUROSCI.0445-14.2014] [PMID: 24672003]
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; 591(18): 4637-53.
[http://dx.doi.org/10.1113/jphysiol.2013.255695] [PMID: 23798494]

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