Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression
Open accessAbstract
Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Increased expression of muscle-specific PGC-1a1 in transgenic mice is associated with greater resilience to chronic stress and stress-induced CNS inflammation.
“increased expression of muscle-specific PGC-1a1 in transgenic mice was associated with greater resilience to chronic stress and stress-induced CNS inflammation (Agudelo et al., 2014).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Agudelo et al., 2014
This shift in kynurenine metabolism can protect the brain from stress-induced depression.
“This shift in kynurenine metabolism is able to protect the brain from stress-induced depression150.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [150]
Evidence is accumulating that factors released from non-neuronal tissue and delivered to the brain via the vasculature may have important roles in synaptic plasticity, memory function and mood regulation.
“Evidence is now accumulating that factors released from non-neuronal tissue148–152 and delivered via the vasculature to the brain might have important roles in synaptic plasticity, memory function and mood regulation150.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [150]
In mice and humans, chronic aerobic training increases muscle expression of kynurenine aminotransferase, which facilitates conversion of kynurenine to kynurenic acid, a metabolite unable to cross the blood-brain barrier.
“In both mice and humans, chronic aerobic training increases muscle expression of kynurenine aminotransferase, which facilitates conversion of kynurenine into kynurenic acid, a metabolite that is unable to cross the blood-brain barrier.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [150]
Cites
The rat brain in stereotaxic coordinates
Palkovits, M. (1983) · Neuropeptides · doi:10.1016/0143-4179(83)90049-5 · Cited by 28,988 · see citing works
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395 · see citing works
Whiteford, H. A., Degenhardt, L., Rehm, J., Baxter, A. J., Ferrari, A. J., Erskine, H. E., Charlson, F. J., Norman, R. E., Flaxman, A. D., Johns, N., et al. (2013) · The Lancet · doi:10.1016/s0140-6736(13)61611-6 · Cited by 6,006 · see citing works
A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis
Boström, P., Wu, J., Jedrychowski, M. P., Korde, A., Ye, L., Lo, J. C., Rasbach, K. A., Boström, E. A., Choi, J. H., Long, J. Z., et al. (2012) · Nature · doi:10.1038/nature10777 · Cited by 4,810 · see citing works
Depression: a new animal model sensitive to antidepressant treatments
PORSOLT, R. D., LE PICHON, M., & JALFRE, M. (1977) · Nature · doi:10.1038/266730a0 · Cited by 4,451 · see citing works
A Neurotrophic Model for Stress-Related Mood Disorders
Duman, R. S., & Monteggia, L. M. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.02.013 · Cited by 3,375 · see citing works
Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres
Lin, J., Wu, H., Tarr, P. T., Zhang, C.-Y., Wu, Z., Boss, O., Michael, L. F., Puigserver, P., Isotani, E., Olson, E. N., et al. (2002) · Nature · doi:10.1038/nature00904 · Cited by 2,546 · see citing works
Metabolic control through the PGC-1 family of transcription coactivators
Lin, J., Handschin, C., & Spiegelman, B. M. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.004 · Cited by 2,130 · see citing works
Synaptic Dysfunction in Depression: Potential Therapeutic Targets
Duman, R. S., & Aghajanian, G. K. (2012) · Science · doi:10.1126/science.1222939 · Cited by 1,651 · see citing works
Willner, P. (2005) · Neuropsychobiology · doi:10.1159/000087097 · Cited by 1,605 · see citing works
Assessing antidepressant activity in rodents: recent developments and future needs
Cryan, J. F., Markou, A., & Lucki, I. (2002) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(02)02017-5 · Cited by 1,551 · see citing works
Kynurenines in the mammalian brain: when physiology meets pathology
Schwarcz, R., Bruno, J. P., Muchowski, P. J., & Wu, H.-Q. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3257 · Cited by 1,530 · see citing works
Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway
Wrann, C. D., White, J. P., Salogiannnis, J., Laznik-Bogoslavski, D., Wu, J., Ma, D., Lin, J. D., Greenberg, M. E., & Spiegelman, B. M. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.09.008 · Cited by 1,440 · see citing works
Smith, M., Makino, S., Květňanský, R., & Post, R. M. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-03-01768.1995 · Cited by 1,429 · see citing works
Epidemiology of depression and diabetes: a systematic review
Roy, T., & Lloyd, C. E. (2012) · Journal of Affective Disorders · doi:10.1016/s0165-0327(12)70004-6 · Cited by 1,229 · see citing works
Regulation of Muscle Fiber Type and Running Endurance by PPARδ
Wang, Y.-X., Zhang, C.-L., Yu, R. T., Cho, H. K., Nelson, M. C., Bayuga-Ocampo, C. R., Ham, J., Kang, H., & Evans, R. M. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020294 · Cited by 1,089 · see citing works
Towards a glutamate hypothesis of depression
Sanacora, G., Treccani, G., & Popoli, M. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.07.036 · Cited by 1,036 · see citing works
Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1
Baar, K., Wende, A. R., Jones, T. E., Marison, M., Nolte, L. A., Chen, M., Kelly, D. P., & Holloszy, J. O. (2002) · The FASEB Journal · doi:10.1096/fj.02-0367com · Cited by 1,020 · see citing works
Lawlor, D. A., & Hopker, S. W. (2001) · BMJ · doi:10.1136/bmj.322.7289.763 · Cited by 995 · see citing works
Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle
Barrès, R., Yan, J., Egan, B., Treebak, J. T., Rasmussen, M., Fritz, T., Caidahl, K., Krook, A., O'Gorman, D. J., & Zierath, J. R. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.01.001 · Cited by 965 · see citing works
Self-citationDecreased expression of synapse-related genes and loss of synapses in major depressive disorder
Kang, H. J., Voleti, B., Hajszan, T., Rajkowska, G., Stockmeier, C. A., Licznerski, P., Lepack, A., Majik, M. S., Jeong, L. S., Banasr, M., et al. (2012) · Nature Medicine · doi:10.1038/nm.2886 · Cited by 808 · see citing works
Blood–Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism
Fukui, S., Schwarcz, R. M., Rapoport, S. I., Takada, Y., & Smith, Q. R. (1991) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1991.tb03460.x · Cited by 765 · see citing works
(2000) · PubMed · Cited by 685 · see citing works
A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy
Ruas, J. L., White, J. P., Rao, R. R., Kleiner, S., Brannan, K. T., Harrison, B. C., Greene, N. P., Wu, J., Estall, J. L., Irving, B. A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.050 · Cited by 677 · see citing works
Self-citationThe immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression
Müller, N., & Schwarz, M. J. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4002006 · Cited by 670 · see citing works
Short, K. R., Vittone, J. L., Bigelow, M. L., Proctor, D. N., Rizza, R. A., Coenen-Schimke, J. M., & Nair, K. S. (2003) · Diabetes · doi:10.2337/diabetes.52.8.1888 · Cited by 631 · see citing works
Gliogenesis and Glial Pathology in Depression
Rajkowska, G., & Miguel-Hidalgo, J. J. (2007) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152707780619326 · Cited by 612 · see citing works
Handschin, C., Chin, S., Li, P., Liu, F., Maratos-Flier, E., LeBrasseur, N. K., Yan, Z., & Spiegelman, B. M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704817200 · Cited by 611 · see citing works
Yuen, E. Y., Wei, J., Liu, W., Zhong, P., Li, X., & Yan, Z. (2012) · Neuron · doi:10.1016/j.neuron.2011.12.033 · Cited by 558 · see citing works
Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders
Kheirbek, M., Klemenhagen, K. C., Sahay, A., & Hen, R. (2012) · Nature Neuroscience · doi:10.1038/nn.3262 · Cited by 543 · see citing works
Banasr, M., Chowdhury, G. M. I., Terwilliger, R., Newton, S. S., Duman, R. S., Behar, K. L., & Sanacora, G. (2010) · Molecular Psychiatry · doi:10.1038/mp.2008.106 · Cited by 458 · see citing works
Behavioral stress impairs long-term potentiation in rodent hippocampus
Foy, M. R., Stanton, M. E., Levine, S., & Thompson, R. F. (1987) · Behavioral and Neural Biology · doi:10.1016/s0163-1047(87)90664-9 · Cited by 436 · see citing works
Czéh, B., Simon, M., Schmelting, B., Hiemke, C., & Fuchs, E. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300982 · Cited by 434 · see citing works
Metabolic signatures of exercise in human plasma
Lewis, G. D., Farrell, L., Wood, M. J., Martinovic, M., Arany, Z., Rowe, G. C., Souza, A., Cheng, S., McCabe, E. L., Yang, E., et al. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3001006 · Cited by 432 · see citing works
The Role of Exercise-Induced Myokines in Muscle Homeostasis and the Defense against Chronic Diseases
Brandt, C., & Pedersen, B. K. (2010) · BioMed Research International · doi:10.1155/2010/520258 · Cited by 426 · see citing works
The transcriptional coactivator PGC-1α mediates exercise-induced angiogenesis in skeletal muscle
Chinsomboon, J., Ruas, J., Gupta, R. K., Thom, R., Shoag, J., Rowe, G. C., Sawada, N., Raghuram, S., & Arany, Z. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909131106 · Cited by 379 · see citing works
Self-citationl-Kynurenine Its synthesis and possible regulatory function in brain
G�l, E. M., & Sherman, A. D. (1980) · Neurochemical Research · doi:10.1007/bf00964611 · Cited by 318 · see citing works
Inflammation, Glutamate, and Glia in Depression:<i>A Literature Review</i>
McNally, L., Bhagwagar, Z., & Hannestad, J. (2008) · CNS Spectrums · doi:10.1017/s1092852900016734 · Cited by 289 · see citing works
Choi, C. S., Befroy, D. E., Codella, R., Kim, S., Reznick, R. M., Hwang, Y.-J., Liu, Z.-X., Lee, H.-Y., Distefano, A., Samuel, V. T., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810339105 · Cited by 279 · see citing works
Facilitated physical activity as a treatment for depressed adults: randomised controlled trial
Chalder, M., Wiles, N., Campbell, J., Hollinghurst, S., Haase, A., Taylor, A. H., Fox, K., Costelloe, C., Searle, A., Baxter, H., et al. (2012) · British medical journal · doi:10.1136/bmj.e2758 · Cited by 264 · see citing works
Depression and type 2 diabetes: Inflammatory mechanisms of a psychoneuroendocrine co-morbidity
Stuart, M. J., & Baune, B. T. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.10.001 · Cited by 257 · see citing works
Oxenkrug, G. F. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8497-4 · Cited by 255 · see citing works
PGC-1 coactivators and skeletal muscle adaptations in health and disease
Arany, Z. P. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2008.07.018 · Cited by 244 · see citing works
McClintock, S. M., Husain, M. M., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Trivedi, M. H., Cook, I., Morris, D., Warden, D., & Rush, A. J. (2011) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e31820ebd2c · Cited by 234 · see citing works
Skeletal muscle aging and the mitochondrion
Johnson, M. L., Robinson, M. M., & Nair, K. S. (2013) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2012.12.003 · Cited by 233 · see citing works
Network beyond IDO in psychiatric disorders: Revisiting neurodegeneration hypothesis
Myint, A.-M., & Kim, Y.-K. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.08.008 · Cited by 230 · see citing works
Gibney, S. M., McGuinness, B. W., Prendergast, C., Harkin, A., & Connor, T. J. (2012) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2012.11.010 · Cited by 220 · see citing works
Depression‐resistant endophenotype in mice overexpressing cannabinoid CB <sub>2</sub> receptors
García‐Gutiérrez, M., Pérez‐Ortiz, J., Gutiérrez‐Adán, A., & Manzanares, J. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00819.x · Cited by 196 · see citing works
Neuronal network plasticity and recovery from depression
Castrén, E. (2013) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.1 · Cited by 190 · see citing works
Neuroimmunological effects of physical exercise in depression
Eyre, H. A., & Baune, B. T. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.09.015 · Cited by 188 · see citing works
Eisele, P. S., Salatino, S., Sobek, J., Hottiger, M. O., & Handschin, C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.375253 · Cited by 187 · see citing works
Running is rewarding and antidepressive
Brené, S., Bjørnebekk, A., Åberg, E., Mathé, A. A., Olson, L., & Werme, M. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.05.015 · Cited by 172 · see citing works
Tochigi, M., Iwamoto, K., Bundo, M., Sasaki, T., Kato, N., & Kato, T. (2007) · Neuroscience Research · doi:10.1016/j.neures.2007.10.010 · Cited by 156 · see citing works
Bechtholt, A. J., Walther, H. V., Adams, M. A., Carlezon, W. A., Öngür, D., & Cohen, B. M. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.74 · Cited by 152 · see citing works
Liu, W., Sheng, H., Xu, Y., Liu, Y., Lu, J., & Ni, X. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.12.041 · Cited by 143 · see citing works
Dysfunctional hippocampal activity affects emotion and cognition in mood disorders
Femenía, T., Gómez-Galán, M., Lindskog, M., & Magara, S. (2012) · Brain Research · doi:10.1016/j.brainres.2012.03.053 · Cited by 143 · see citing works
Self-citationDysfunctional astrocytic regulation of glutamate transmission in a rat model of depression
Gómez‐Galán, M., Bundel, D. D., Eeckhaut, A. V., Smolders, I. J., & Lindskog, M. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.10 · Cited by 123 · see citing works
Self-citationFroger, N., Palazzo, E., Boni, C., Hanoun, N., Saurini, F., Joubert, C., Dutriez-Casteloot, I., Enache, M., Maccari, S., Barden, N., et al. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4132-03.2004 · Cited by 123 · see citing works
[23] Punch sampling biopsy technique
Palkovits, M. (1983) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(83)03025-6 · Cited by 119 · see citing works
Inflammatory Factors Contribute to Depression and Its Comorbid Conditions
Anisman, H., & Hayley, S. P. (2012) · Science Signaling · doi:10.1126/scisignal.2003579 · Cited by 117 · see citing works
Schmitt, B., Flück, M., Décombaz, J., Kreis, R., Boesch, C., Wittwer, M., Graber, F., Vogt, M., HOWALD, H., & Hoppeler, H. H. (2003) · Physiological Genomics · doi:10.1152/physiolgenomics.00089.2003 · Cited by 103 · see citing works
Differential expression of stress proteins in human adult astrocytes in response to cytokines
Bajramovic, J. J., Bsibsi, M., Geutskens, S. B., et al. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(99)00260-x · Cited by 102 · see citing works
Gibb, J., Hayley, S. P., Poulter, M. O., & Anisman, H. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.11.008 · Cited by 94 · see citing works
Disorders of memory and plasticity in psychiatric disease
Pittenger, C. (2013) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2013.15.4/cpittenger · Cited by 92 · see citing works
Wu, H., Okuyama, M., Kajii, Y., Pocivavsek, A., Bruno, J. P., & Schwarcz, R. M. (2014) · Schizophrenia Bulletin · doi:10.1093/schbul/sbt157 · Cited by 78 · see citing works
Lloyd, R. B., & Nemeroff, C. B. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026611109060609 · Cited by 67 · see citing works
Claes, S., Myint, A.-M., Domschke, K., Del-Favero, J., Entrich, K., Engelborghs, S., De Deyn, P., Mueller, N., Baune, B., & Rothermundt, M. (2011) · Psychiatry Research · doi:10.1016/j.psychres.2011.03.012 · Cited by 65 · see citing works
Postnatal development and plasticity of specialized muscle fiber characteristics in the hindlimb
Garry, D. J., Bassel‐Duby, R., Richardson, J. A., Grayson, J. M., Neufer, P. D., & Williams, R. S. (1996) · Developmental Genetics · doi:10.1002/(sici)1520-6408(1996)19:2 · Cited by 58 · see citing works
Dissecting the genetic effect of the CRH system on anxiety and stress-related behaviour
Deussing, J. M., & Wurst, W. (2005) · Comptes Rendus Biologies · doi:10.1016/j.crvi.2005.01.001 · Cited by 49 · see citing works
Thermal stability, pH dependence and inhibition of four murine kynurenine aminotransferases
Han, Q., Cai, T., Tagle, D., & Li, J.-Y. (2010) · BMC Biochemistry · doi:10.1186/1471-2091-11-19 · Cited by 38 · see citing works
Mahoney, D. J., & Tarnopolsky, M. A. (2005) · Physical Medicine and Rehabilitation Clinics of North America · doi:10.1016/j.pmr.2005.08.018 · Cited by 29 · see citing works
Strenuous physical exercise adversely affects monocyte chemotaxis
Caidahl, K., Olieslagers, S., Krook, A., Rickenlund, A. M., Rickenlund, A. M., Zierath, J. R., Czepluch, F. S., Barrès, R., & Waltenberger, J. L. (2010) · Thrombosis and Haemostasis · doi:10.1160/th10-06-0363 · Cited by 22 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286 · see citing works
Howard, D. M., Adams, M. J., Clarke, T.-K., Hafferty, J. D., Gibson, J., Shirali, M., Coleman, J. R. I., Hagenaars, S. P., Ward, J., Wigmore, E. M., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0326-7 · Cited by 2,565 · see citing works
Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants
Duman, R. S., Aghajanian, G. K., Sanacora, G., & Krystal, J. H. (2016) · Nature Medicine · doi:10.1038/nm.4050 · Cited by 1,750 · see citing works
Integrative Biology of Exercise
Hawley, J. A., Hargreaves, M., Joyner, M. J., & Zierath, J. R. (2014) · Cell · doi:10.1016/j.cell.2014.10.029 · Cited by 1,152 · see citing works
Self-citationExerkines in health, resilience and disease
Chow, L. S., Gerszten, R. E., Taylor, J. M., Pedersen, B. K., van Praag, H., Trappe, S., Febbraio, M. A., Galis, Z. S., Gao, Y., Haus, J. M., et al. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00641-2 · Cited by 927 · see citing works
Self-citationPhysical activity and muscle-brain crosstalk
Pedersen, B. K. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0174-x · Cited by 772 · see citing works
Role of Inactivity in Chronic Diseases: Evolutionary Insight and Pathophysiological Mechanisms
Booth, F. W., Roberts, C. K., Thyfault, J. P., Ruegsegger, G. N., & Toedebusch, R. G. (2017) · Physiological Reviews · doi:10.1152/physrev.00019.2016 · Cited by 696 · see citing works
Ruegsegger, G. N., & Booth, F. W. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a029694 · Cited by 690 · see citing works
Running-induced systemic cathepsin B secretion is associated with memory function
Moon, H. Y., Becke, A., Berron, D., Becker, B., Sah, N., Benoni, G., Janke, E., Lubejko, S. T., Greig, N. H., Mattison, J. A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.025 · Cited by 628 · see citing works
Molecular mechanisms linking exercise to cancer prevention and treatment
Hojman, P., Gehl, J., Christensen, J. F., & Pedersen, B. K. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.09.015 · Cited by 600 · see citing works
Molecular Choreography of Acute Exercise
Contrepois, K., Wu, S., Moneghetti, K. J., Hornburg, D., Ahadi, S., Tsai, M.-S., Metwally, A. A., Wei, E., Lee-McMullen, B., Quijada, J. V., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.043 · Cited by 502 · see citing works
Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise
Schnyder, S., & Handschin, C. (2015) · Bone · doi:10.1016/j.bone.2015.02.008 · Cited by 419 · see citing works
Skeletal Muscle as an Endocrine Organ: The Role of Myokines in Exercise Adaptations
Hoffmann, C., & Weigert, C. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a029793 · Cited by 393 · see citing works
Microbiota alteration is associated with the development of stress-induced despair behavior
Marin, I. A., Goertz, J. E., Ren, T., Rich, S. S., Onengut-Gumuscu, S., Farber, E., Wu, M., Overall, C. C., Kipnis, J., & Gaultier, A. (2017) · Scientific Reports · doi:10.1038/srep43859 · Cited by 369 · see citing works
Exercise benefits on Alzheimer’s disease: State-of-the-science
Valenzuela, P. L., Castillo-García, A., Morales, J. S., de la Villa, P., Hampel, H., Emanuele, E., Lista, S., & Lucia, A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101108 · Cited by 337 · see citing works
Zhu, F., Guo, R., Wang, W., Ju, Y., Wang, Q., Ma, Q., Sun, Q., Fan, Y., Xie, Y., Yang, Z., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0475-4 · Cited by 323 · see citing works
Can physical exercise in old age improve memory and hippocampal function?
Duzel, E., van Praag, H., & Sendtner, M. (2016) · Brain · doi:10.1093/brain/awv407 · Cited by 329 · see citing works
Exercise Metabolism and Adaptation in Skeletal Muscle
Smith, J. A. B., Murach, K. A., Dyar, K. A., & Zierath, J. R. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00606-x · Cited by 342 · see citing works
Self-citationAn exercise-inducible metabolite that suppresses feeding and obesity
Li, V. L., He, Y., Contrepois, K., Liu, H., Kim, J. T., Wiggenhorn, A. L., Tanzo, J. T., Tung, A. S.-H., Lyu, X., Zushin, P.-J. H., et al. (2022) · Nature · doi:10.1038/s41586-022-04828-5 · Cited by 331 · see citing works
Kynurenine pathway in depression: a systematic review and meta-analysis
Ogyu, K., Kubo, K., Noda, Y., Iwata, Y., Tsugawa, S., Omura, Y., Wada, M., Tarumi, R., Plitman, E., Moriguchi, S., et al. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.03.023 · Cited by 301 · see citing works
Probiotic Supplementation in Patients with Alzheimer’s Dementia - An Explorative Intervention Study
Leblhuber, F., Steiner, K., Schuetz, B., Fuchs, D., & Gostner, J. M. (2018) · Current Alzheimer Research · doi:10.2174/1389200219666180813144834 · Cited by 269 · see citing works
Cerniauskas, I., Winterer, J., de Jong, J. W., Lukacsovich, D., Yang, H., Khan, F., Peck, J. R., Obayashi, S. K., Lilascharoen, V., Lim, B. K., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.09.005 · Cited by 187 · see citing works
Exercise training in cancer control and treatment
Christensen, J. F., Simonsen, C., & Hojman, P. (2018) · Comprehensive physiology · doi:10.1002/cphy.c180016 · Cited by 203 · see citing works
Meier, T. B., Drevets, W. C., Wurfel, B. E., Ford, B. N., Morris, H. M., Victor, T. A., Bodurka, J., Teague, T. K., Dantzer, R., & Savitz, J. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.11.003 · Cited by 175 · see citing works
Myokines mediate the cross talk between skeletal muscle and other organs
Chen, W., Wang, L., You, W., & Shan, T. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30033 · Cited by 162 · see citing works
Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation
Miller, A. H., Haroon, E., & Felger, J. C. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.167 · Cited by 152 · see citing works
Strasser, B., Geiger, D., Schauer, M., Gostner, J., Gatterer, H., Burtscher, M., & Fuchs, D. (2016) · Nutrients · doi:10.3390/nu8110752 · Cited by 142 · see citing works
Fuertig, R., Azzinnari, D., Bergamini, G., Cathomas, F., Sigrist, H., Seifritz, E., Vavassori, S., Luippold, A., Hengerer, B., Ceci, A., et al. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.12.020 · Cited by 135 · see citing works
Physical Exercise as Treatment for PTSD: A Systematic Review and Meta-Analysis
Björkman, F., & Ekblom, Ö. (2022) · Military Medicine · doi:10.1093/milmed/usab497 · Cited by 131 · see citing works
Systemic Nutrient and Stress Signaling via Myokines and Myometabolites
Rai, M., & Demontis, F. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105305 · Cited by 123 · see citing works
Fahimi, A., Baktir, M. A., Moghadam, S., Mojabi, F. S., Sumanth, K., McNerney, M. W., Ponnusamy, R., & Salehi, A. (2017) · Brain Structure and Function · doi:10.1007/s00429-016-1308-8 · Cited by 94 · see citing works
Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression
Kim, Y.-K., & Na, K.-S. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.03.009 · Cited by 84 · see citing works
Can exercise training teach us how to treat Alzheimer's disease?
Huuha, A. M., Norevik, C. S., Moreira, J. B. N., Kobro-Flatmoen, A., Scrimgeour, N., Kivipelto, M., Van Praag, H., Ziaei, M., Sando, S. B., Wisløff, U., et al. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101559 · Cited by 79 · see citing works
Wu, Y., Dong, J.-H., Dai, Y.-F., Zhu, M.-Z., Wang, M.-Y., Zhang, Y., Pan, Y.-D., Yuan, X.-R., Guo, Z.-X., Wang, C.-X., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.06.002 · Cited by 84 · see citing works
Role of dietary protein and muscular fitness on longevity and aging
Strasser, B., Volaklis, K., Fuchs, D., & Burtscher, M. (2018) · Aging and Disease · doi:10.14336/ad.2017.0202 · Cited by 78 · see citing works
Liver Soluble Epoxide Hydrolase Regulates Behavioral and Cellular Effects of Chronic Stress
Qin, X.-H., Wu, Z., Dong, J.-H., Zeng, Y.-N., Xiong, W.-C., Liu, C., Wang, M.-Y., Zhu, M.-Z., Chen, W.-J., Zhang, Y., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.006 · Cited by 80 · see citing works
Coping with Stress During Aging: The Importance of a Resilient Brain
Sampedro-Piquero, P., Alvarez-Suarez, P., & Begega, A. (2018) · Current Neuropharmacology · doi:10.2174/1570159x15666170915141610 · Cited by 41 · see citing works
Exercise, fitness, and the gut
Cronin, O., Molloy, M. G., & Shanahan, F. (2016) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000240 · Cited by 47 · see citing works
Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis
Bianchi, A., Marchetti, L., Hall, Z., Lemos, H., Vacca, M., Paish, H., Green, K., Elliott, B., Tiniakos, D., Passos, J. F., et al. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2001022 · Cited by 45 · see citing works
Zhan, G., Huang, N., Li, S., Hua, D., Zhang, J., Fang, X., Yang, N., Luo, A., & Yang, C. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5041-2 · Cited by 32 · see citing works
Chbeir, S., & Carrión, V. (2023) · World Journal of Psychiatry · doi:10.5498/wjp.v13.i5.144 · Cited by 25 · see citing works
Javelle, F., Laborde, S., Hosang, T. J., Metcalfe, A. J., & Zimmer, P. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.623946 · Cited by 25 · see citing works
Obesity and Exercise: New Insights and Perspectives
James, N. M., & Stanford, K. I. (2025) · Endocrine Reviews · doi:10.1210/endrev/bnaf017 · Cited by 20 · see citing works
- Authors
- Agudelo, L. Z., Femenía, T., Orhan, F., Porsmyr-Palmertz, M., Goiny, M., Martinez-Redondo, V., Correia, J. C., Izadi, M., Bhat, M., Schuppe-Koistinen, I., Pettersson, A. T., Ferreira, D. M. S., Krook, A., Barres, R., Zierath, J. R., Erhardt, S., Lindskog, M., & Ruas, J. L.
- Affiliations
- Karolinska Institutet (SE)
- Science for Life Laboratory (SE)
- Corresponding author
- Lindskog, Maria
- Ruas, Jorge L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 159
- Issue
- 1
- Pages
- 33-45
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2117415152
- Cited by
- 739
- References
- 73
- Citations by year
- 2026: 62 · 2025: 64 · 2024: 75 · 2023: 58 · 2022: 64 · 2021: 76 · 2020: 71 · 2019: 64 · 2018: 52 · 2017: 39 · 2016: 50 · 2015: 56 · 2014: 7
- FWCI
- 15.50
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-01-15)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- HAL (submittedVersion)
- Funders
- AstraZeneca
- Novo Nordisk Fonden (NNF12OC1016062)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- kynurenine metabolism, kynurenic acid, kynurenine aminotransferase, skeletal muscle, exercise training, stress-induced depression, chronic mild stress, blood-brain barrier, transgenic mice, depression treatment
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Transaminases, Animals, Blood-Brain Barrier, Depression, Humans, Kynurenic Acid, Kynurenine, Physical Conditioning, Animal, Stress, Psychological, Transcription Factors, Muscle, Skeletal, Muscle Fibers, Skeletal, Gene Expression Profiling, PPAR alpha, Mice, Physical Conditioning, Human
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review