Resistance Exercise Enhances Cognitive Function in Mouse

Abstract

Physical exercise has been shown to increase adult neurogenesis in the hippocampus and to enhance synaptic plasticity. It has been demonstrated that these neuroprotective effects can be observed following aerobic exercise. However, it remains unknown whether plasticity molecules, such as brain-derived neurotrophic factor (BDNF) and cyclic AMP response element-binding protein (CREB), are expressed in the hippocampus following resistance exercise. We applied voluntary progressive-resistance wheel exercise (RE) for 14 days, and measured BDNF and CREB in the hippocampus. The Morris water maze was also performed to estimate learning and memory. Furthermore, we measured RE effects on mammalian target of rapamycin (mTOR) and 70-kDa ribosomal protein S6 kinase (p70S6K) mediating muscle protein synthesis in the soleus. As a result, we found that RE enhanced cognition and elevated BDNF and CREB expressions in the hippocampus. Also, RE activated the mTOR-p70S6K signaling pathway in the soleus. We found that phosphorylated mTOR and p70S6K were significantly positively correlated with BDNF expression. Our results indicated that resistance exercise drove the protein synthesis signaling pathway in the soleus and enhanced hippocampal synaptic plasticity-related molecules. These results suggest the beneficial effects of resistance exercise on cognitive function.

Key words

resistance exercise - cognition - brain-derived neurotrophic factor - cyclic AMP response element-binding protein - mammalian target of rapamycin - 70-kDa ribosomal protein S6 kinase

• References

• 1 Abbott RD, White LR, Ross GW, Masaki KH, Curb JD, Petrovitch H. Walking and dementia in physically capable elderly men. JAMA 2004; 292: 1447-1453
• 2 Adams GR. Invited Review: Autocrine/paracrine IGF-I and skeletal muscle adaptation. J Appl Physiol 2002; 93: 1159-1167
• 3 Adlard PA, Cotman CW. Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression. Neuroscience 2004; 124: 985-992
• 4 Aguilar V, Alliouachene S, Sotiropoulos A, Sobering A, Athea Y, Djouadi F, Miraux S, Thiaudiere E, Foretz M, Viollet B, Diolez P, Bastin J, Benit P, Rustin P, Carling D, Sandri M, Ventura-Clapier R, Pende M. S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase. Cell Metab 2007; 5: 476-487
• 5 Allen DL, Harrison BC, Maass A, Bell ML, Byrnes WC, Leinwand LA. Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. J Appl Physiol 2001; 90: 1900-1908
• 6 Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yancopoulos GD. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 2001; 3: 1014-1019
• 7 Booth FW, Tseng BS, Fluck M, Carson JA. Molecular and cellular adaptation of muscle in response to physical training. Acta Physiol Scand 1998; 162: 343-350
• 8 Chen MJ, Russo-Neustadt AA. Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus 2009; 19: 962-972
• 9 Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci 2003; 14: 125-130
• 10 Colcombe SJ, Erickson KI, Raz N, Webb AG, Cohen NJ, McAuley E, Kramer AF. Aerobic fitness reduces brain tissue loss in aging humans. J Gerontol A Biol Sci Med Sci 2003; 58: 176-180
• 11 Colcombe SJ, Kramer AF, Erickson KI, Scalf P, McAuley E, Cohen NJ, Webb A, Jerome GJ, Marquez DX, Elavsky S. Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci USA 2004; 101: 3316-3321
• 12 Conti AC, Cryan JF, Dalvi A, Lucki I, Blendy JA. cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs. J Neurosci 2002; 22: 3262-3268
• 13 Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002; 25: 295-301
• 14 Cotman CW, Berchtold NC. Physical activity and the maintenance of cognition: learning from animal models. Alzheimers Dement 2007; 3: S30-S37
• 15 Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiat 2006; 59: 1116-1127
• 16 Dwivedi Y, Rizavi HS, Pandey GN. Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: differential regulation of specific exons by antidepressants and corticosterone. Neuroscience 2006; 139: 1017-1029
• 17 Erickson KI, Raji CA, Lopez OL, Becker JT, Rosano C, Newman AB, Gach HM, Thompson PM, Ho AJ, Kuller LH. Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study. Neurology 2010; 75: 1415-1422
• 18 Fuss J, Ben Abdallah NM, Vogt MA, Touma C, Pacifici PG, Palme R, Witzemann V, Hellweg R, Gass P. Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis. Hippocampus 2010; 20: 364-376
• 19 Goekint M, De Pauw K, Roelands B, Njemini R, Bautmans I, Mets T, Meeusen R. Strength training does not influence serum brain-derived neurotrophic factor. Eur J Appl Physiol 2010; 110: 285-293
• 20 Gomez-Pinilla F, Huie JR, Ying Z, Ferguson AR, Crown ED, Baumbauer KM, Edgerton VR, Grau JW. BDNF and learning: Evidence that instrumental training promotes learning within the spinal cord by up-regulating BDNF expression. Neuroscience 2007; 148: 893-906
• 21 Gomez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol 2002; 88: 2187-2195
• 22 Greenwood BN, Strong PV, Foley TE, Thompson RS, Fleshner M. Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus. Neuroscience 2007; 144: 1193-1208
• 23 Griffin EW, Bechara RG, Birch AM, Kelly AM. Exercise enhances hippocampal-dependent learning in the rat: evidence for a BDNF-related mechanism. Hippocampus 2009; 19: 973-980
• 24 Harriss DJ, Atkinson G. Update – ethical standards in sport and exercise science research. Int J Sports Med 2011; 32: 819-821
• 25 Haskell WL, Lee IM, Pate RR, Powell KE, Blair SN, Franklin BA, Macera CA, Heath GW, Thompson PD, Bauman A. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc 2007; 39: 1423-1434
• 26 Ishihara A, Hirofuji C, Nakatani T, Itoh K, Itoh M, Katsuta S. Effects of running exercise with increasing loads on tibialis anterior muscle fibres in mice. Exp Physiol 2002; 87: 113-116
• 27 Ishihara A, Roy RR, Ohira Y, Ibata Y, Edgerton VR. Hypertrophy of rat plantaris muscle fibers after voluntary running with increasing loads. J Appl Physiol 1998; 84: 2183-2189
• 28 Johnson RA, Rhodes JS, Jeffrey SL, Garland Jr T, Mitchell GS. Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running. Neuroscience 2003; 121: 1-7
• 29 Konhilas JP, Widegren U, Allen DL, Paul AC, Cleary A, Leinwand LA. Loaded wheel running and muscle adaptation in the mouse. Am J Physiol 2005; 289: H455-H465
• 30 Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane P, Kukull W. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med 2006; 144: 73-81
• 31 Levinger I, Goodman C, Matthews V, Hare DL, Jerums G, Garnham A, Selig S. BDNF, metabolic risk factors, and resistance training in middle-aged individuals. Med Sci Sports Exerc 2008; 40: 535-541
• 32 Molteni R, Ying Z, Gomez-Pinilla F. Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarray. Eur J Neurosci 2002; 16: 1107-1116
• 33 Morris RG, Garrud P, Rawlins JN, O’Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature 1982; 297: 681-683
• 34 Nelson ME, Rejeski WJ, Blair SN, Duncan PW, Judge JO, King AC, Macera CA, Castaneda-Sceppa C. Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc 2007; 39: 1435-1445
• 35 Nichol KE, Parachikova AI, Cotman CW. Three weeks of running wheel exposure improves cognitive performance in the aged Tg2576 mouse. Behav Brain Res 2007; 184: 124-132
• 36 Nishijima T, Piriz J, Duflot S, Fernandez AM, Gaitan G, Gomez-Pinedo U, Verdugo JM, Leroy F, Soya H, Nunez A, Torres-Aleman I. Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron 2010; 67: 834-846
• 37 Ohanna M, Sobering AK, Lapointe T, Lorenzo L, Praud C, Petroulakis E, Sonenberg N, Kelly PA, Sotiropoulos A, Pende M. Atrophy of S6K1(-/-) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control. Nat Cell Biol 2005; 7: 286-294
• 38 Pallafacchina G, Calabria E, Serrano AL, Kalhovde JM, Schiaffino S. A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc Natl Acad Sci U S A 2002; 99: 9213-9218
• 39 Radak Z, Toldy A, Szabo Z, Siamilis S, Nyakas C, Silye G, Jakus J, Goto S. The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain. Neurochem Int 2006; 49: 387-392
• 40 Schiffer T, Schulte S, Hollmann W, Bloch W, Struder HK. Effects of strength and endurance training on brain-derived neurotrophic factor and insulin-like growth factor 1 in humans. Horm Metab Res 2009; 41: 250-254
• 41 Schweitzer NB, Alessio HM, Berry SD, Roeske K, Hagerman AE. Exercise-induced changes in cardiac gene expression and its relation to spatial maze performance. Neurochem Int 2006; 48: 9-16
• 42 Shen H, Tong L, Balazs R, Cotman CW. Physical activity elicits sustained activation of the cyclic AMP response element-binding protein and mitogen-activated protein kinase in the rat hippocampus. Neuroscience 2001; 107: 219-229
• 43 Soya H, Nakamura T, Deocaris CC, Kimpara A, Iimura M, Fujikawa T, Chang H, McEwen BS, Nishijima T. BDNF induction with mild exercise in the rat hippocampus. Biochem Biophys Res Commun 2007; 358: 961-967
• 44 Stranahan AM, Lee K, Martin B, Maudsley S, Golden E, Cutler RG, Mattson MP. Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice. Hippocampus 2009; 19: 951-961
• 45 Sutherland RJ, Kolb B, Whishaw IQ. Spatial mapping: definitive disruption by hippocampal or medial frontal cortical damage in the rat. Neurosci Lett 1982; 31: 271-276
• 46 Tong L, Shen H, Perreau VM, Balazs R, Cotman CW. Effects of exercise on gene-expression profile in the rat hippocampus. Neurobiol Dis 2001; 8: 1046-1056
• 47 van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 2005; 25: 8680-8685
• 48 Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 2004; 20: 2580-2590
• 49 Vaynman S, Ying Z, Gomez-Pinilla F. The select action of hippocampal calcium calmodulin protein kinase II in mediating exercise-enhanced cognitive function. Neuroscience 2007; 144: 825-833
• 50 Yaffe K, Barnes D, Nevitt M, Lui LY, Covinsky K. A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch Intern Med 2001; 161: 1703-1708
• 51 Yarrow JF, White LJ, McCoy SC, Borst SE. Training augments resistance exercise induced elevation of circulating brain derived neurotrophic factor (BDNF). Neurosci Lett 2010; 479: 161-165