Molecular mechanisms underlying the beneficial effects of exercise on brain function and neurological disorders

Journal article

Nay, Kévin, Smiles, William J., Kaiser, Jacqueline, McAloon, Luke M., Loh, Kim, Galic, Sandra, Oakhill, Jonathan S., Gundlach, Andrew L. and Scott, John W.. (2021). Molecular mechanisms underlying the beneficial effects of exercise on brain function and neurological disorders. International Journal of Molecular Sciences. 22, p. Article 4052. https://doi.org/10.3390/ijms22084052
AuthorsNay, Kévin, Smiles, William J., Kaiser, Jacqueline, McAloon, Luke M., Loh, Kim, Galic, Sandra, Oakhill, Jonathan S., Gundlach, Andrew L. and Scott, John W.
Abstract

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle–brain, liver–brain and gut–brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise–brain communication and their benefits for physiology and brain function.

Keywordsexercise; brain; BDNF; iron; microbiota; Alzheimer’s disease; Parkinson’s disease
Year2021
JournalInternational Journal of Molecular Sciences
Journal citation22, p. Article 4052
PublisherMultidisciplinary Digital Publishing Institute (MDPI AG)
ISSN1422-0067
Digital Object Identifier (DOI)https://doi.org/10.3390/ijms22084052
PubMed ID33919972
Scopus EID2-s2.0-85104000770
PubMed Central IDPMC8070923
Open accessPublished as ‘gold’ (paid) open access
Research or scholarlyResearch
Page range1-18
FunderNational Health and Medical Research Council (NHMRC)
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication dates
Online14 Apr 2021
Publication process dates
Accepted12 Apr 2021
Deposited14 Mar 2022
Grant IDNHMRC/1138102
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Loh, Kim, Tam, Shanna, Murray-Segal, Lisa, Huynh, Kevin, Meikle, Peter J., Scott, John W., van Denderen, Bryce J., Chen, Zhiping, Steel, Rohan, LeBlond, Nicholas D., Burkovsky, Leah A., O'Dwyer, Conor, Nunes, Julia R. C., Steinberg, Gregory R., Fullerton, Morgan D., Galic, Sandra and Kemp, Bruce E.. (2019). Inhibition of adenosine monophosphate-activated protein kinase-3-hydroxy-3-methylglutaryl coenzyme a reductase signaling leads to hypercholesterolemia and promotes hepatic steatosis and insulin resistance. Hepatology Communications. 3(1), pp. 84 - 98. https://doi.org/10.1002/hep4.1279
Transient expression of AMPK heterotrimer complexes in mammalian cells
Jon Oakhill, John Scott and Toby A. Dite. (2018). Transient expression of AMPK heterotrimer complexes in mammalian cells. In AMPK pp. 159-169 Humana Press, Inc.. https://doi.org/10.1007/978-1-4939-7598-3_10
Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion
Lindqvist, Lisa M., Frank, Daniel, McArthur, Kate, Dite, Toby A., Lazarou, Michael, Oakhill, Jon, Kile, Benjamin T. and Vaux, David L.. (2018). Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion. Cell Death and Differentiation. 25(4), pp. 782 - 794. https://doi.org/10.1038/s41418-017-0017-z
Mitochondrial MDM2 regulates respiratory complex i activity independently of p53
Arena, Giuseppe, Cissé, Madi Yann, Pyrdziak, Samuel, Chatre, Laurent, Riscal, Romain, Fuentes, Maryse, Arnold, Jamie Jon, Kastner, Markus, Gayte, Laurie, Bertrand-Gaday, Christelle, Nay, Kevin, Angebault-Prouteau, Claire, Murray, Kerren, Chabi, Beatrice, Koechlin-Ramonatxo, Christelle, Orsetti, Béatrice, Vincent, Charles, Casas, François, Marine, Jean-Christophe, ... Le Cam, Laurent. (2018). Mitochondrial MDM2 regulates respiratory complex i activity independently of p53. Molecular Cell. 69(4), pp. 594 - 609. https://doi.org/10.1016/j.molcel.2018.01.023
Structural determinants for small-molecule activation of skeletal muscle AMPK α2β2γ1 by the glucose importagog sc4
Ngoei, Kevin R.W., Langendorf, Christopher G., Ling, Naomi, Hoque, Ashfaqul, Johnson, Swapna, Camerino, Michelle C., Walker, Scott R., Bozikis, Ylva E., Dite, Toby A., Ovens, Ashley J., Smiles, William, Jacobs, Roxane, Huang, He, Parker, Michael W., Scott, John W., Rider, Mark H., Foitzik, Richard C., Kemp, Bruce, Baell, Jonathan B. and Oakhill, Jonathan S.. (2018). Structural determinants for small-molecule activation of skeletal muscle AMPK α2β2γ1 by the glucose importagog sc4. Cell Chemical Biology. 25(6), pp. 728 - 737. https://doi.org/10.1016/j.chembiol.2018.03.008
The guardian of the genome p53 regulates exercise-induced mitochondrial plasticity beyond organelle biogenesis
Smiles, William and Camera, Donny. (2018). The guardian of the genome p53 regulates exercise-induced mitochondrial plasticity beyond organelle biogenesis. Acta Physiologica. 222(3), pp. 1 - 13. https://doi.org/10.1111/apha.13004
Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells
Hoque, Ashfaqul, Sivakumaran, Priyadharshini, Bond, Simon T., Ling, Naomi, Kong, Anne M., Scott, John W., Bandara, Nadeeka, Hernandez, Damian, Liu, Guei-Sheung, Wong, Raymond, Ryan, Michael T., Hausenloy, Derek, Kemp, Bruce, Oakhill, Jonathan S., Drew, Brian, Pebay, Alice and Lim, Shiang Y.. (2018). Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells. Cell Death Discovery. 4(39), pp. 1 - 13. https://doi.org/10.1038/s41420-018-0042-9
AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965
Dite, Toby A., Langendorf, Christopher, Hoque, Ashfaqul, Galic, Sandra, Rebello, Richard J., Ovens, Ashley J., Lindqvist, Lisa M., Ngoei, Kevin R.W., Ling, Naomi, Furic, Luc, Kemp, Bruce, Scott, John W. and Oakhill, Jonathan S.. (2018). AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965. Journal of Biological Chemistry. 293(23), pp. 8874 - 8885. https://doi.org/10.1074/jbc.RA118.003547
1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors
Asquith, Christopher R.M., Godoi, Paulo H., Counago, Rafael M., Laitinen, Tuomo, Scott, John W., Langendorf, Christopher G., Oakhill, Jonathan S., Drewry, David H., Zuercher, William J., Koutentis, Panayiotis A., Willson, Timothy M. and Kalogirou, Andreas S.. (2018). 1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors. Molecules. 23(5), pp. 1 - 23. https://doi.org/10.3390/molecules23051221
Fenugreek increases insulin-stimulated creatine content in l6C11 muscle myotubes
Tomcik, Kristyen, Smiles, William, Camera, Donny, Hugel, Helmut M., Hawley, John and Watts, Rani. (2017). Fenugreek increases insulin-stimulated creatine content in l6C11 muscle myotubes. European Journal of Nutrition. 56(3), pp. 973 - 979. https://doi.org/10.1007/s00394-015-1145-1
Acute low-intensity cycling with blood-flow restriction has no effect on metabolic signaling in human skeletal muscle compared to traditional exercise
Smiles, William J., Conceição, Miguel S., Telles, Guilherme D., Chacon-Mikahil, Mara P. T., Cavaglieri, Cláudia R., Vechin, Felipe C., Libardi, Cleiton A., Hawley, John A. and Camera, Donny M.. (2017). Acute low-intensity cycling with blood-flow restriction has no effect on metabolic signaling in human skeletal muscle compared to traditional exercise. European Journal of Applied Physiology. 117(2), pp. 345-358. https://doi.org/10.1007/s00421-016-3530-8
Impact of genetic variation on human CaMKK2 regulation by Ca2+ -calmodulin and multisite phosphorylation
O'Brien, Matthew, Oakhill, Jonathan S., Ling, Naomi, Langendorf, Christopher G., Hoque, Ashfaqul, Dite, Toby A., Means, Anthony R., Kemp, Bruce and Scott, John W.. (2017). Impact of genetic variation on human CaMKK2 regulation by Ca2+ -calmodulin and multisite phosphorylation. Scientific Reports. 7, pp. 1 - 11. https://doi.org/10.1038/srep43264
The sweet side of AMPK signaling: Regulation of GFAT1
Scott, John W. and Oakhill, Jonathan S.. (2017). The sweet side of AMPK signaling: Regulation of GFAT1. Biochemical Journal. 474(7), pp. 1289 - 1292. https://doi.org/10.1042/BCJ20170006
The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
Dite, Toby A., Ling, Naomi, Scott, John W., Hoque, Ashfaqul, Galic, Sandra, Parker, Benjamin L., Ngoei, Kevin R.W., Langendorf, Christopher G., O'Brien, Matthew, Kundu, Mondira, Viollet, Benoit, Steinberg, Gregory R., Sakamoto, Kei, Kemp, Bruce and Oakhill, Jonathan S.. (2017). The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs. Nature Communications. 8(571), pp. 1 - 14. https://doi.org/10.1038/s41467-017-00628-y
Fake inhibitors: AMPK activation trumps inhibition
Langendorf, Christopher G., Scott, John W. and Kemp, Bruce E.. (2017). Fake inhibitors: AMPK activation trumps inhibition. Cell Chemical Biology. 24(7), pp. 775 - 777. https://doi.org/10.1016/j.chembiol.2017.07.005
Dynamic proteome profiling of individual proteins in human skeletal muscle after a high-fat diet and resistance exercise
Camera, Donny M., Burniston, Jatin G., Pogson, Mark A., Smiles, William J. and Hawley, John A.. (2017). Dynamic proteome profiling of individual proteins in human skeletal muscle after a high-fat diet and resistance exercise. The FASEB Journal. 31(12), pp. 5478-5494. https://doi.org/10.1096/fj.201700531R
Autophagy and Protein Turnover Responses to Exercise-Nutrient Interactions in Human Skeletal Muscle
Smiles, William J.. (2017). Autophagy and Protein Turnover Responses to Exercise-Nutrient Interactions in Human Skeletal Muscle [Thesis]. https://doi.org/10.4226/66/59f29efd01e38
Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans
Laker, R. C., Garde, C., Camera, Donny, Smiles, William, Zierath, J. R., Hawley, John and Barrès, R.. (2017). Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans. Scientific Reports. 7(1), pp. 1 - 12. https://doi.org/10.1038/s41598-017-15420-7
Cyclin-dependent kinase-mediated phosphorylation of breast cancer metastasis suppressor 1 (BRMS1) affects cell migration
Roesley, Siti Nur Ain, Suryadinata, Randy, Morrish, Emma, Tan, Anthonius Ricardo, Issa, Samah M. A., Oakhill, Jon, Bernard, Ora, Welch, Danny R. and Sarcevic, Boris. (2016). Cyclin-dependent kinase-mediated phosphorylation of breast cancer metastasis suppressor 1 (BRMS1) affects cell migration. Cell Cycle. 15(1), pp. 137 - 151. https://doi.org/10.1080/15384101.2015.1121328
Acute endurance exercise induces nuclear p53 abundance in human skeletal muscle
Tachtsis, Bill, Smiles, William, Lane, Steven C., Hawley, John Alan and Camera, Donny Michael. (2016). Acute endurance exercise induces nuclear p53 abundance in human skeletal muscle. Frontiers in Physiology. 7(144), pp. 1 - 10. https://doi.org/10.3389/fphys.2016.00144
Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding
Langendorf, Christopher G., Ngoei, Kevin R. W., Scott, John W., Ling, Naomi X. Y., Issa, Sam M. A., Gorman, Michael A., Parker, Michael W., Sakamoto, Kei, Oakhill, Jonathan S. and Kemp, Bruce Ernest. (2016). Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding. Nature Communications. 7, pp. 1 - 8. https://doi.org/10.1038/ncomms10912
Exercise-induced skeletal muscle signaling pathways and human athletic performance
Camera, Donny Michael, Smiles, William J. and Hawley, John Alan. (2016). Exercise-induced skeletal muscle signaling pathways and human athletic performance. Free Radical Biology & Medicine. 98, pp. 131 - 143. https://doi.org/10.1016/j.freeradbiomed.2016.02.007
Effects of skeletal muscle energy availability on protein turnover responses to exercise
Smiles, William J., Hawley, John Alan and Camera, Donny Michael. (2016). Effects of skeletal muscle energy availability on protein turnover responses to exercise. Journal of Experimental Biology. 219(Pt 2), pp. 214 - 225. https://doi.org/10.1242/jeb.125104
Protein coingestion with alcohol following strenuous exercise attenuates alcohol-induced intramyocellular apoptosis and inhibition of autophagy
Smiles, William J., Parr, Evelyn B., Coffey, Vernon G., Lacham-Kaplan, Orly, Hawley, John Alan and Camera, Donny Michael. (2016). Protein coingestion with alcohol following strenuous exercise attenuates alcohol-induced intramyocellular apoptosis and inhibition of autophagy. American Journal of Physiology - Endocrinology and Metabolism. 311(5), pp. E836 - E849. https://doi.org/10.1152/ajpendo.00303.2016
The social supply of cannabis among young people in Australia
Lenton, Simon, Grigg, Jodie, Scott, John, Barratt, Monica and Eleftheriadis, Dina. (2015). The social supply of cannabis among young people in Australia. Trends and Issues in Crime and Criminal Justice. (503), pp. 1-6.
Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity
Ford, Rebecca, Fullerton, Morgan, Pinkosky, Stephen, Day, Emily, Scott, John, Oakhill, Jonathan, Bujak, Adam, Smith, Brennan, Crane, Justin, Blumer, Regje, Marcinko, Katarina, Kemp, Bruce, Gerstein, Hertzel and Steinberg, Gregory. (2015). Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity. Biochemical Journal. 468(1), pp. 125 - 132. https://doi.org/10.1042/BJ20150125
Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release
Scott, John, Galic, Sandra, Graham, Kate, Foitzik, Richard, Ling, Naomi, Dite, Toby, Issa, Samah, Langendorf, Chris, Weng, Qing, Thomas, Helen, Kay, Thomas, Birnberg, Neal, Steinberg, Gregory, Kemp, Bruce and Oakhill, Jonathan. (2015). Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release. Chemistry and Biology. 22(6), pp. 705 - 711. https://doi.org/10.1016/j.chembiol.2015.05.011
Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder
Scott, John, Park, Elizabeth, Rodriguiz, Ramona, Oakhill, Jonathan, Issa, Samah, O'Brien, Matthew, Dite, Toby, Langendorf, Christopher, Wetsel, William, Means, Anthony and Kemp, Bruce. (2015). Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder. Scientific Reports. 5, pp. 1 - 10. https://doi.org/10.1038/srep14436
SnRK1 from Arabidopsis thaliana is an atypical AMPK
Emanuelle, Shane, Hossain, Mohammed Iqbal, Moller, Isabel E., Pedersen, Henriette L., van de Meene, Allison M. L., Doblin, Monika S., Koay, Ann, Oakhill, Jonathan S., Scott, John W., Willats, William G. T., Kemp, Bruce Ernest, Bacic, Antony, Gooley, Paul R. and Stapleton, David I.. (2015). SnRK1 from Arabidopsis thaliana is an atypical AMPK. Plant Journal. 82(2), pp. 183 - 192. https://doi.org/10.1111/tpj.12813
Mutant TDP-43 deregulates AMPK activation by PP2A in ALS models
Perera, Nirma, Sheean, Rebecca, Scott, John, Kemp, Bruce, Horne, Malcolm and Turner, Bradley. (2014). Mutant TDP-43 deregulates AMPK activation by PP2A in ALS models. PLoS One (online). 9(3), pp. 1 - 11. https://doi.org/10.1371/journal.pone.0090449
The relationship between exercise, nutrition and type 2 diabetes
Stephenson, Erin J., Smiles, William and Hawley, John Alan. (2014). The relationship between exercise, nutrition and type 2 diabetes. Medicine and Sport Science. 60, pp. 1 - 10. https://doi.org/10.1159/000357331
ATP sensitive bi-quinoline activator of the AMP-activated protein kinase
Scott, John, Oakhill, Jonathan, Ling, Naomi, Langendorf, Christopher, Foitzik, Richard, Kemp, Bruce and Issinger, Olaf-Georg. (2014). ATP sensitive bi-quinoline activator of the AMP-activated protein kinase. Biochemical and Biophysical Research Communications. 443(2), pp. 435 - 440. https://doi.org/10.1016/j.bbrc.2013.11.130
Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling
Scott, John, Ling, Naomi, Issa, Samah, Dite, Toby, O'Brien, Matthew, Chen, Zhi-Ping, Galic, Sandra, Langendorf, Christopher, Steinberg, Gregory, Kemp, Bruce and Oakhill, Jonathan. (2014). Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Chemistry and Biology. 21(5), pp. 619 - 627. https://doi.org/10.1016/j.chembiol.2014.03.006
Differences between first episode schizophrenia and schizoaffective disorder
Cotton, Sue, Lambert, M, Schimmelmann, B, Mackinnon, Andrew, Gleeson, John, Berk, Michael, Hides, L, Chanen, Andrew, Scott, J and Schottle, D. (2013). Differences between first episode schizophrenia and schizoaffective disorder. Schizophrenia Research. https://doi.org/10.1016/j.schres.2013.02.036
Ca 2+/calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation
Green, Michelle, Scott, John, Steel, Rohan, Oakhill, Jonathan, Kemp, Bruce and Means, Anthony. (2011). Ca 2+/calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation. Journal of Biological Chemistry. 286(32), pp. 28066 - 28079. https://doi.org/10.1074/jbc.M111.251504
AMPK is a direct adenylate charge-regulated protein kinase
Oakhill, Jonathan S., Steel, Rohan, Chen, Zhi-Ping, Scott, John W., Ling, Naomi, Tam, Shanna and Kemp, Bruce Ernest. (2011). AMPK is a direct adenylate charge-regulated protein kinase. Science. 332(6036), pp. 1433 - 1435. https://doi.org/10.1126/science.1200094