Increasing evidence shows that exercise training is neuroprotective after stroke, but the underlying mechanisms are unknown. To clarify this critical issue, the current study investigated the effects of early treadmill exercise on the expression of mitochondrial biogenesis factors. Adult rats were subjected to ischemia induced by middle cerebral artery occlusion followed by reperfusion. Expression of two genes critical for transcriptional regulation of mitochondrial biogenesis, peroxisome proliferator-activated receptor coactivator-1 (PGC-1) and nuclear respiratory factor-1 (NRF-1), were examined by RT-PCR after five days of exercise starting at 24 h after ischemia. Mitochondrial protein cytochrome C oxidase subunit IV (COX IV) was detected by Western blot. Neurological status and cerebral infarct volume were evaluated as indices of brain damage. Treadmill training increased levels of PGC-1 and NRF-1 mRNA, indicating that exercise promotes rehabilitation after ischemia via regulation of mitochondrial biogenesis.
References
[1]
Chung, J.Y.; Kim, M.W.; Bang, M.S.; Kim, M. The effect of exercise on trkA in the contralateral hemisphere of the ischemic rat brain. Brain Res 2010, 1353, 187–193.
[2]
DeBow, S.B.; Davies, M.A.; Clarke, H.L.; Colbourne, F. Constraint-induced movement therapy and rehabilitation exercises lessen motor deficits and volume of brain injury after striatal hemorrhagic stroke in rats. Stroke 2003, 34, 1021–1026.
[3]
Marin, R.; Williams, A.; Hale, S.; Burge, B.; Mense, M.; Bauman, R.; Tortella, F. The effect of voluntary exercise exposure on histological and neurobehavioral outcomes after ischemic brain injury in the rat. Physiol. Behav 2003, 80, 167–175.
[4]
Yang, Y.R.; Wang, R.Y.; Wang, P.S.; Yu, S.M. Treadmill training effects on neurological outcome after middle cerebral artery occlusion in rats. Can. J. Neurol. Sci 2003, 30, 252–258.
Hood, D.A.; Saleem, A. Exercise-induced mitochondrial biogenesis in skeletal muscle. Nutr. Metab. Cardiovasc. Dis 2007, 17, 332–337.
[7]
Wright, D.C.; Han, D.H.; Garcia-Roves, P.M.; Geiger, P.C.; Jones, T.E.; Holloszy, J.O. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J. Biol. Chem 2007, 282, 194–199.
[8]
Steiner, J.L.; Murphy, E.A.; McClellan, J.L.; Carmichael, M.D.; Davis, J.M. Exercise training increases mitochondrial biogenesis in the brain. J. Appl. Physiol 2011, 111, 1066–1071.
[9]
Bayod, S.; del Valle, J.; Canudas, A.M.; Lalanza, J.F.; Sanchez-Roigé, S.; Camins, A.; Escorihuela, R.M.; Pallas, M. Long-term treadmill exercise induces neuroprotective molecular changes in rat brain. J. Appl. Physiol 2011, 111, 1380–1390.
[10]
Yin, W.; Signore, A.P.; Iwai, M.; Cao, G.; Gao, Y.; Chen, J. Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke 2008, 39, 3057–3063.
[11]
Valerio, A.; Bertolotti, P.; Delbarba, A.; Perego, C.; Dossena, M.; Ragni, M.; Spano, P.; Carruba, M.O.; de Simoni, M.G.; Nisoli, E. Glycogen synthase kinase-3 inhibition reduces ischemic cerebral damage, restores impaired mitochondrial biogenesis and prevents ROS production. J. Neurochem 2011, 116, 1148–1159.
[12]
Pyoria, O.; Talvitie, U.; Nyrkko, H.; Kautiainen, H.; Pohjolainen, T.; Kasper, V. The effect of two physiotherapy approaches on physical and cognitive functions and independent coping at home in stroke rehabilitation. A preliminary follow-up study. Disabil. Rehabil. 2007, 29, 503–511.
[13]
Langhammer, B.; Lindmark, B.; Stanghelle, J.K. Stroke patients and long-term training: Is it worthwhile? A randomized comparison of two different training strategies after rehabilitation. Clin. Rehabil 2007, 21, 495–510.
[14]
Gertz, K.; Priller, J.; Kronenberg, G.; Fink, K.B.; Winter, B.; Schr?ck, H.; Ji, S.; Milosevic, M.; Harms, C.; B?hm, M.; Dirnagl, U.; Laufs, U.; Endres, M. Physical activity improves long-term stroke outcome via endothelial nitric oxide synthase-dependent augmentation of neovascularization and cerebral blood flow. Circ. Res 2006, 99, 1132–1140.
[15]
Moseley, A.M.; Stark, A.; Cameron, I.D.; Pollock, A. Treadmill training and body weight support for walking after stroke. Cochrane Database Syst. Rev 2005, 19, doi:10.1161/01.STR.0000102415.43108.66.
[16]
Ohlsson, A.L.; Johansson, B.B. The environment influences functional outcome of cerebral infarction in rats. Stroke 1995, 26, 644–649.
[17]
Yang, Y.R.; Wang, R.Y.; Wang, P.S. Early and late treadmill training after focal brain ischemia in rats. Neurosci. Lett 2003, 339, 91–94.
[18]
Risedal, A.; Zeng, J.; Johansson, B.B. Early training may exacerbate brain damage after focal brain ischemia in the rat. J. Cereb. Blood Flow Metab 1999, 19, 997–1003.
[19]
Lanza, I.R.; Sreekumaran Nair, K. Regulation of skeletal muscle mitochondrial function: Genes to proteins. Acta Physiol 2010, 199, 529–547.
[20]
Ljubicic, V.; Joseph, A.M.; Saleem, A.; Uguccioni, G.; Collu-Marchese, M.; Lai, R.Y.; Nguyen, L.M.; Hood, D.A. Transcriptional and post-transcriptional regulation of mitochondrial biogenesis in skeletal muscle: Effects of exercise and aging. Biochim. Biophys. Acta 2010, 1800, 223–234.
[21]
McLeod, C.; Pagel, I.; Sack, M. The mitochondrial biogenesis regulatory program in cardiac adaptation to ischemia—A putative target for therapeutic intervention. Trends Cardiovasc 2005, 15, 118–123.
[22]
Onyango, I.G.; Lu, J.; Rodova, M.; Lezi, E.; Crafter, A.B.; Swerdlow, R.H. Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim. Biophys. Acta 2010, 1802, 228–234.
[23]
Vi?a, J.; Gomez-Cabrera, M.C.; Borras, C.; Froio, T.; Sanchis-Gomar, F.; Martinez-Bello, V.E.; Pallardo, F.V. Mitochondrial biogenesis in exercise and in ageing. Adv. Drug Deliv. Rev 2009, 61, 1369–1374.
[24]
Hood, D.A. Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle. Appl. Physiol. Nutr. Metab 2009, 34, 465–472.
[25]
Longa, E.Z.; Weinstein, P.R.; Carlson, S.; Cummins, R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989, 20, 84–91.
[26]
Rogers, D.C.; Campbell, C.A.; Stretton, J.L.; Mackay, K.B. Correlation between motor impairment and infarct volume after permanent and transient middle cerebral artery occlusion in the rat. Stroke 1997, 28, 2060–2066.
[27]
Jia, J.; Hu, Y.S.; Wu, Y.; Liu, G.; Yu, H.X.; Zheng, Q.P.; Zhu, D.N.; Xia, C.M.; Cao, Z.J. Pre-ischemic treadmill training affects glutamate and gamma aminobutyric acid levels in the striatal dialysate of a rat model of cerebral ischemia. Life Sci 2009, 84, 505–511.
[28]
DiFiglia, M.; Sapp, E.; Chase, K.; Schwarz, C.; Meloni, A.; Young, C.; Martin, E.; Vonsattel, J.P.; Carraway, R.; Reeves, S.A. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 1995, 14, 1075–1081.