The DOI matches its Crossref record; 57 of the 58 references it cites were found in a registry or an index.
Exercise, Serum Free Tryptophan, and Central Fatigue
Open accessAbstract
Brain tryptophan (TRP) concentrations and serotonin (5HT) synthesis and release increase during running. This increase in 5HT function may promote central fatigue and contribute to suboptimal physical performance. The rise in brain TRP is reputed to result from exercise-induced elevations in serum nonesterified fatty acid (NEFA) concentrations, which dissociate TRP from albumin in blood and increase the serum free TRP pool. But, as discussed in this article, ample evidence exists that the serum free TRP pool does not control brain TRP uptake. The clearest data are dietary, but pharmacologic data in exercising rats also support this conclusion. Changes in the serum levels of amino acids that compete with TRP for brain uptake appear also not to explain the rise in brain TRP. The mechanism is therefore not presently known. The link between the rise in brain TRP and 5HT synthesis/release is not simple: a rise in brain TRP stimulates 5HT synthesis/release in actively firing neurons. Hence, during exercise, only 5HT neurons that are firing should increase 5HT production/release when brain TRP rises. It is not known which 5HT neurons fire during exercise; the 5HT neurons that respond to exercise-induced increases in brain TRP are therefore not known. Hence, it is not possible to conclude which 5HT neurons contribute to the generation of central fatigue. Because some 5HT neurons control specific functions important to physical performance (e.g., respiration), the current understanding of 5HT neuronal function in central fatigue might benefit from the study of specific 5HT pathways during exercise.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
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?
In the citing paper
“Large doses of simple antioxidant mixtures or individual vitamins are not recommended and may be toxic. Athletes should obtain antioxidants from an increased consumption of fruits and vegetables [95].”
From Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes (2016) · cites this paper as [95]
Citations
Cites
Spinal and Supraspinal Factors in Human Muscle Fatigue
Gandevia, S. C. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.4.1725 · Cited by 3,855
Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection
Oldendorf, W. (1971) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1971.221.6.1629 · Cited by 1,691
Brain Serotonin Content: Physiological Dependence on Plasma Tryptophan Levels
Fernstrom, J. D., & Wurtman, R. J. (1971) · Science · doi:10.1126/science.173.3992.149 · Cited by 1,017
Self-citationPUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect
Tunaru, S., Kero, J. T., Schaub, A., Wufka, C., Blaukat, A., Pfeffer, K., & Offermanns, S. (2003) · Nature Medicine · doi:10.1038/nm824 · Cited by 801
Brain Serotonin Content: Increase Following Ingestion of Carbohydrate Diet
Fernstrom, J. D., & Wurtman, R. J. (1971) · Science · doi:10.1126/science.174.4013.1023 · Cited by 734
Self-citationPossible mechanisms of central nervous system fatigue during exercise
Davis, J. M., & Bailey, S. P. (1997) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-199701000-00008 · Cited by 686
Supraspinal factors in human muscle fatigue: evidence for suboptimal output from the motor cortex.
Gandevia, S. C., Allen, G. M., Butler, J. E., & Taylor, J. L. (1996) · The Journal of Physiology · doi:10.1113/jphysiol.1996.sp021164 · Cited by 681
The Specific Binding of l-Tryptophan to Serum Albumin
McMenamy, R. H., & Oncley, J. L. (1958) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)49353-2 · Cited by 640
Anatomy of the Serotonergic Systema
Törk, I. (1990) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1990.tb16870.x · Cited by 557
Serotonergic neurons as carbon dioxide sensors that maintain ph homeostasis
Richerson, G. B. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1409 · Cited by 519
Role of precursor availability in control of monoamine biosynthesis in brain.
Fernstrom, J. D. (1983) · Physiological Reviews · doi:10.1152/physrev.1983.63.2.484 · Cited by 491
Self-citationSerotonergic facilitation of facial motoneuron excitation
McCall, R. B., & Aghajanian, G. K. (1979) · Brain Research · doi:10.1016/0006-8993(79)90370-6 · Cited by 445
Schmidt, B. J., & Jordan, L. M. (2000) · Brain Research Bulletin · doi:10.1016/s0361-9230(00)00402-0 · Cited by 425
Veasey, S., Fornal, C. A., Metzler, C. W., & Jacobs, B. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-07-05346.1995 · Cited by 402
Free Tryptophan in Plasma and Brain Tryptophan Metabolism
Knott, P. J., & Curzon, G. (1972) · Nature · doi:10.1038/239452a0 · Cited by 378
Adrenergic regulation of lipolysis in situ at rest and during exercise.
Arner, P., Kriegholm, E., Engfeldt, P., & Bolinder, J. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114516 · Cited by 373
Hjorth, S., & Magnusson, T. (1988) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/bf00179315 · Cited by 302
Blood-Brain Barrier Carrier-Mediated Transport and Brain Metabolism of Amino Acids
Pardridge, W. M. (1998) · Neurochemical Research · doi:10.1023/a:1022482604276 · Cited by 287
Effects of acute physical exercise on central serotonergic systems
CHAOULOFF, F. (1997) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-199701000-00009 · Cited by 275
Serotonin and central nervous system fatigue: nutritional considerations
Davis, J. M., Alderson, N. L., & WELSH, R. S. (2000) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/72.2.573s · Cited by 268
Free tryptophan in serum controls brain tryptophan level and serotonin synthesis
Tagliamonte, A., Biggio, G., Vargiu, L., & Gessa, G. L. (1973) · Life Sciences · doi:10.1016/0024-3205(73)90361-5 · Cited by 265
Blomstrand, E., Perrett, D. I., Parry‐Billings, M., & Newsholme, E. A. (1989) · Acta Physiologica Scandinavica · doi:10.1111/j.1748-1716.1989.tb08689.x · Cited by 217
Relevance of free tryptophan in serum to tissue tryptophan concentrations
Madras, B. K., Cohen, E. L., Messing, R. B., Munro, H. N., & Wurtman, R. J. (1974) · Metabolism · doi:10.1016/0026-0495(74)90027-4 · Cited by 161
Chaouloff, F., Elghozi, J., Guezennec, Y., & Laude, D. (1985) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1985.tb09432.x · Cited by 160
Amino acids and central fatigue
Blomstrand, E. (2001) · Amino Acids · doi:10.1007/s007260170063 · Cited by 160
Unbound Amino Acid Concentrations in Human Blood Plasmas
McMenamy, R. H., Lund, C. C., & Oncley, J. L. (1957) · Journal of Clinical Investigation · doi:10.1172/jci103568 · Cited by 153
Strüder, H., Hollmann, W., Platen, P., Donike, M., Gotzmann, A., & Weber, K. (1998) · Hormone and Metabolic Research · doi:10.1055/s-2007-978864 · Cited by 147
MEEUSEN, R. R., Thorré, K., Chaouloff, F., Sarre, S., Meirleir, K. D., Ebinger, G., & Michotte, Y. M. (1996) · Brain Research · doi:10.1016/s0006-8993(96)00872-4 · Cited by 141
Veasey, S. C., Fornal, C. A., Metzler, C. W., & Jacobs, B. L. (1997) · Neuroscience · doi:10.1016/s0306-4522(96)00673-2 · Cited by 132
Chaouloff, F., Kennett, G. A., Serrurrier, B., Mérino, D., & Curzon, G. (1986) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1986.tb01789.x · Cited by 128
Lipsett, D., Madras, B. K., Wurtman, R. J., & Munro, H. N. (1973) · Life Sciences · doi:10.1016/0024-3205(73)90027-1 · Cited by 108
Physiological responses to short-term exercise in the heat after creatine loading
VOLEK, J. S., MAZZETTI, S. A., FARQUHAR, W. B., BARNES, B. R., GÓMEZ, A. L., & KRAEMER, W. J. (2001) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-200107000-00006 · Cited by 105
Transport of Tryptophan into Brain from the Circulating, Albumin‐Bound Pool in Rats and in Rabbits
Pardridge, W. M., & Fierer, G. (1990) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1990.tb02345.x · Cited by 96
Chaouloff, F., Laude, D., & Elghozi, J. (1989) · Journal of Neural Transmission · doi:10.1007/bf01252498 · Cited by 96
Acworth, I. N., Nicholass, J. M., Morgan, B., & Newsholme, E. A. (1986) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(86)91188-5 · Cited by 91
Dietary Carbohydrate Increases Brain Tryptophan and Decreases Free Plasma Tryptophan
Madras, B. K., Cohen, E. L., Fernstrom, J. D., Larin, F., Munro, H. N., & Wurtman, R. J. (1973) · Nature · doi:10.1038/244034a0 · Cited by 89
Self-citationHassmén, P., Blomstrand, E., Ekblom, B. T., & Newsholme, E. A. (1994) · PubMed · Cited by 85
Sharp, T., Bramwell, S., & Smith, A. D. (1992) · Life Sciences · doi:10.1016/0024-3205(92)90321-f · Cited by 71
Fernstrom, J. D., Hirsch, M. J., & Faller, D. V. (1976) · Biochemical Journal · doi:10.1042/bj1600589 · Cited by 65
Self-citationModulation of ventilatory control during exercise
Turner, D. L., Bach, K. B., MARTIN, P. A., Olsen, E., Brownfield, M. S., Foley, K. T., & Mitchell, G. S. (1997) · Respiration Physiology · doi:10.1016/s0034-5687(97)00093-5 · Cited by 54
Raphé-produced excitation of spinal cord motoneurons in the cat
Fung, S. J., & Barnes, C. D. (1989) · Neuroscience Letters · doi:10.1016/0304-3940(89)90573-9 · Cited by 53
Calders, P., Matthys, D., Derave, W., & Pannier, J. L. (1999) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-199904000-00015 · Cited by 49
Activation of tryptophan hydroxylase by stimulation of central serotonergic neurons
Boadle‐Biber, M. C., Johannessen, J. N., Narasimhachari, N., & Phan, T.-H. (1983) · Biochemical Pharmacology · doi:10.1016/0006-2952(83)90678-0 · Cited by 46
Gerin, C. G., Legrand, A., & Privat, A. (1994) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(94)90121-x · Cited by 42
Kinetics of Elimination of Drugs Possessing High Affinity for the Plasma Proteins
MARTIN, B. K. (1965) · Nature · doi:10.1038/207959a0 · Cited by 42
Curzon, G., & Knott, P. J. (1975) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1975.tb07580.x · Cited by 41
Pharmacological Evidence that Stimulation of Central Serotonergic Pathways Increases Renin Secretion
Zimmermann, H., & Ganong, W. F. (2008) · Neuroendocrinology · doi:10.1159/000122983 · Cited by 40
Curzon, G., & Fernando, J. C. R. (1976) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1976.tb08621.x · Cited by 34
Fernstrom, M. H., Massoudi, M. S., & Fernstrom, J. D. (1990) · Life Sciences · doi:10.1016/0024-3205(90)90585-f · Cited by 31
Self-citationSmriga, M., Kameishi, M., Tanaka, T., Kondoh, T., & Torii, K. (2002) · Nutritional Neuroscience · doi:10.1080/10284150290028936 · Cited by 28
Fernstrom, M. H., & Fernstrom, J. D. (1993) · Life Sciences · doi:10.1016/0024-3205(93)90525-8 · Cited by 27
Self-citationCharacteristics of Tryptophan Binding in the Serum of the Newborn Rat
Bourgoin, S., Faivre‐Bauman, A., Hery, F., Ternaux, J., & Hamon, M. (2009) · Biology of the Neonate · doi:10.1159/000240955 · Cited by 26
Role of brain serotonergic pathways and hypothalamus in regulation of renin secretion
Gotoh, E., Murakami, K., Bahnson, T. D., & Ganong, W. F. (1987) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1987.253.1.r179 · Cited by 24
Baumann, P., & Perey, M. (1977) · Clinica Chimica Acta · doi:10.1016/0009-8981(77)90100-0 · Cited by 20
FOREBRAIN PATHWAYS MEDIATING STRESS‐INDUCED RENIN SECRETION
de Kar, L. D. V. (1996) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.1996.tb02591.x · Cited by 15
Effects of tryptophan depletion on central and peripheral chemoreflexes in man
Struzik, L., Duffin, J., Vermani, M., Hegadoren, K., & Katzman, M. A. (2002) · Respiratory Physiology & Neurobiology · doi:10.1016/s1569-9048(02)00170-2 · Cited by 14
Potential role for nonesterified fatty acids in β-adrenoceptor-induced increases in brain tryptophan
Lenard, N. R., & Dunn, A. J. (2004) · Neurochemistry International · doi:10.1016/j.neuint.2004.07.010 · Cited by 4
Research works printed but not linked: 2
- Tagliamonte, 1971, Possible role of “free” plasma tryptophan in controlling brain tryptophan concentrations, Riv Farmacol Ter., 2, 251
- Martin, 1999, Relationship between medullary serotonergic neuronal activity and diminished motor capacity in awake cats, Soc Neurosci Abstr., 25, 175
Cited by
Sorted by citations
Serotonin, tryptophan metabolism and the brain-gut-microbiome axis
O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G., & Cryan, J. F. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.027 · Cited by 2,012
Jenkins, T., Nguyen, J., Polglaze, K., & Bertrand, P. (2016) · Nutrients · doi:10.3390/nu8010056 · Cited by 904
Kynurenine pathway metabolism and the microbiota-gut-brain axis
Kennedy, P. J., Cryan, J. F., Dinan, T. G., & Clarke, G. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.07.002 · Cited by 724
Clark, A., & Mach, N. (2016) · Journal of the International Society of Sports Nutrition · doi:10.1186/s12970-016-0155-6 · Cited by 583
“Nevertheless, Fernstrom et al [95] state that the central fatigue hypothesis is weak because there lacks evidence that shows what specifically causes an increase in brain tryptophan during exercise [95].”
BackgroundInfluentialMechanisms of Cancer-Related Fatigue
Ryan, J. L., Carroll, J. K., Ryan, E. P., Mustian, K. M., Fiscella, K. A., & Morrow, G. R. (2007) · The Oncologist · doi:10.1634/theoncologist.12-s1-22 · Cited by 599
Metadata
- Authors
- Fernstrom, J. D., & Fernstrom, M. H.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Fernstrom, John D
- Venue
- The Journal of Nutrition
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 136
- Issue
- 2
- Pages
- 553S-559S
- ISSN
- 0022-3166 (ISSN-L)
- OpenAlex
- W1933839043
- Cited by
- 117
- References
- 58
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 9 · 2015: 3 · 2014: 7 · 2013: 4 · 2012: 11
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Keywords
- central fatigue, brain tryptophan, serotonin synthesis, serotonin release, physical activity, free fatty acids, amino acid competition, serotonergic neurons, physical performance, running
- MeSH terms
- Animals, Brain, Fatigue, Fatty Acids, Nonesterified, Neurons, Niacin, Physical Conditioning, Animal, Serotonin, Tryptophan, Rats
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
