r
Medical Hypotheses
MedicalUypofheses(1991) 34, 146148 0 Longman Group UK Ltd 1991
Hypotheses to Explain the Association Between Vigorous Physical Activity and Amyotrophic Lateral Sclerosis W.T. LONGSTRETH*t,
L.M. NELSON? T.D. KOEPSELL*
and G. VAN BELLE5
Neuroepidemiolog y Group, Division of Neurology, Department of Medicine, School of Medicine, ZA - 95, Harborview Medical Center, 325 Ninth Avenue, Seattle, WA 98 104 - 2499, USA. Departments of i Epidemiology, * Health Services, and 5 Biostatistics, School of Public Health and Community Medicine, University of Washington, Seattle, Washington, USA (Reprint requests to WTL) l
Abstract - Many epidemiologic studies indicate a relation between vigorous physical activity and amyotrophic lateral sclerosis. Physical activity itself is unlikely to cause amyotrophic lateral sclerosis, but could it modify the effects of other etiologic factors such as neurotoxins? Vigorous physical activity could potentiate the effect of a toxin to motor neurons by any of several mechanisms, especially if the toxin’s effects were mediated through excitation. Exercise could alter the extent of exposure or could influence the distribution, metabolism or potency of an excitotoxin. Future epidemiologic studies of amyotrophic lateral sclerosis should include sufficient detail about vigorous physical exercise to explore this relationship further.
Introduction Although amyotrophic lateral sclerosis (ALS) is rare, it is devastating. The reported incidence rates range from 0.5 - 2.4 per 100,000 persons per year (1) with a median survival of about two years (2). Rates increase with age and are greater in men than in women (3). A satisfactory treatment is lacking, and risk factors that can be modified have not been identified to guide efforts at prevention. Given that probably 50% or more of motor neurons are destroyed before a patient becomes symptomatic (4), treatments begun at such a late Date received Date accepted
stage may never hold much promise. Epidemiologic studies of risk factors are one approach to guide efforts at prevention. Some interplay among immutable host factors and modifiable environmental and behavioral factors likely determines who will develop ALS. This essay concentrates on vigorous physical activity, a risk factor that has been found consistently in epidemiologic studies of ALS. We know of no mechanism by which vigorous physical activity by itself could cause ALS, so we will seek an explanation for the association by hypothesizing how exercise could modify the effects of a neurotoxin that is
25 May 1990 15 August 1990
144
VIGOROUS
PHYSICAL
ACTIVITY
selective for motor neurons. Evidence is growing that ALS may be caused by exposure to a neurotoxin. Dietary neurotoxins have been proposed to cause lathyrism and Guamanian ALS, both human diseases of motor neurons. A constituent of chickling peas is associated with lathyrism (5), and of the cycad nut with Guamanian ALS (6). Both substances are analogs of alanine, mimic the actions of glutamate, and thus are classified as excitotoxins. In a 1962 conference on ALS, Critchley commented: ‘Nothing has been said about the possible role in aetiology of a previous habit of athleticism. I have the uncomfortable feeling that a past history of unnecessary muscular movement carried out for no obvious reason may be followed in later life by the development of motor neurone disease in a statistically significant number of cases’ (7). Well publicized cases of ALS in athletes, such as baseball’s Lou Gehrig, football’s Matt Hazeltine, boxing’s Ezzard Charles, and others, have also likely contributed to the concept of physical activity as a risk factor. Epidemiologic
evidence
In epidemiologic studies of ALS, vigorous physical activity during work (8 - 13) of leisure time (14, 15, 16) is an association that arises commonly. In the only incident case-control study (IO), the risk of ALS was increased among unskilled workers engaged in heavy labor (odds ratio = 2.0; 95% CI = 1.1 - 3.6). Breland and Currier (11) reported that 50% of men with ALS were heavy laborers in contrast to 30% of male control subjects (computed odds ratio = 2.4; 95% CI = 1.2-4.8). Other studies have reported that the incidence of ALS among heavy laborers is higher than expected based on the number of heavy laborers in the population (9, 12, 13). Felmus and associates (15) reported that ALS cases were significantly more likely to have a history of athletic participation than both healthy and diseased controls: 52% of patients with ALS earned major athletic awards or varsity letters compared with 24% of normal controls. Currier and Conwill (16) conducted a study of 17 twin pairs, one of whom had ALS. The affected member of each pair was more likely to have engaged in a life-long high level of physical activity which extended up to and past the onset of disease. Two studies failed to demonstrate an association between athletic activity and ALS (17, 18). In one (17), controls were childhood and adolescent friends who may have MH
(‘
145
AND ALS
been more likely to engage in the same activities as the cases and thus overmatching of cases and controls may have occurred. In the other (18), information on sports participation was missing for the majority of the cases and controls and thus could have compromised the power of the study. Several studies have identified physical trauma or limb injuries as risk factors for ALS (18-22), but failed to adjust in the analysis for vigorous physical activity, a factor that could predispose an individual to traumatic injury. Other reported risk factors that may also be associated with ALS by virtue of their relation to increased physical activity include male gender (1) and high levels of milk consumption (15, 17, 23). Other factors such as exposure to animal carcasses and hides (24, 25) and to electrical shock (21, 26) seem unrelated to physical activity. Hypotheses
Based on existing knowledge of the pathophysiology of ALS, it is intriguing to consider ways in which physical activity may affect the risk of ALS by modifying the extent or nature of the exposure to a neurotoxin or by influencing its distribution, metabolism or potency. One simple possibility is that an individual is exposed to the toxin during certain physical activities. A fertilizer applied to the playing field is one proposed explanation for why three professional football players from the San Francisco 49ers 1964 team developed ALS. Athletes are also exposed intentionally to other substances. For instance, players on this 1964 team commonly used dimethyl sulfoxide (DMSO) and anabolic steroids (27). DMSO is absorbed through the skin and increases transderma1 absorption of other compounds that would normally not enter the body by this route (28). The anabolic steroids are of note because of the possible importance of the androgens in ALS (29). Androgen receptors are found on those motor neurons that are commonly affected in ALS and are relatively sparse on motor neurons that are spared, such as those innervating the eye muscles (30). In addition to increasing the risk of exposure to a toxin, physical activity could potentiate the effects of the toxin by facilitating its transportation to its target. Vigorous physical activity could affect active transport systems across the bloodbrain barrier. Vigorous physical activity facilitates the uptake by muscle of branched-chain amino acids, namely leucine, isoleucine, and valine (31).
146 These same substances under usual circumstances would compete with other neutral amino acids for active transport across the blood-brain barrier. Glutamine, a potential precursor of glutamate, would also have less competition for transport across the blood-brain barrier during exercise (32). Thus, the potentially damaging effects of excessive glutamate could be increased. Enhanced transport of a hypothetical toxin, structurally or functionally similar to glutamate, could also occur. Tyrosine and tryptophan also compete for the same transport system and during exercise would have easier access to the central nervous system (33). These substances are precursors for the neurotransmitters catecholamine and serotonin, whose actions in descending tracts from the brain stem facilitate excitation of lower motor neurons (34). The actions of an excitotoxin could thus be potentiated. Interestingly, branched-chain amino acids have been proposed as a treatment for ALS and have shown promise in a preliminary randomized trial (35). They are thought to increase glutamate dehydrogenase and thus increase the breakdown of glutamate. If the toxin causing ALS were an analog of glutamate, then a similar beneficial effect of branched-chain amino acids could be expected. Instead of crossing the blood-brain barrier, the toxin could be taken up by the lower motor neuron’s axon and transported retrograde to the cell body, as occurs with the tetanus toxin (36, 37), rabies virus (38) and lead (39). Vigorous exercise that is associated with greater synaptic activity at the neuromuscular junction could cause more toxin to enter the distal axon. Greater synaptic acitivty leads to increased axonal transport (40, 41) that could result in greater amounts of toxin reaching the cell body. Besides these factors, physical activity may make the target cells more susceptible to injury from the toxin. At least one study suggested that motor neurons serving fast-twitch muscle fibers (Type II) were more susceptible in ALS than those to slow-twitch muscle fibers (Type I) (42). Perhaps the lower motor neurons that supply fast twitch fibers are more prone to injury because they fire at three times the rate of motor neurons that supply slow-twitch fibers (43). Physical activities that involve bursts of maximal muscle strength typically engage the fast-twitch fibers which are capable of dramatic hypertrophy; consider the physique of a weight lifter. In contrast, physical activities that involve endurance such as jogging, swimming,
MEDICAL HYPOTHESES
and cycling result in more slow-twitch fiber activity. These fibers have limited capacity for hypertrophy, explaining why marathon runners typically lack the change in physique seen in power athletes. In someone who is sedentary, the fasttwitch fibers may never be activated because the slow-twitch fibers are activated first and may be all that is needed for sedentary activities. If physical activity, especially that involving fast-twitch fibers, is an important factor in developing ALS, then a sedentary person may be relatively resistant to ALS and would require a high dose of exposure to the toxin to develop ALS. Endurance athletes may be more susceptible, but not as susceptible as power athletes. Increased discharges from muscle spindle afferents during vigorous physical activity may also potentiate the effects of a toxin. A typical limb muscle contains a mixture of the usual extrafusal fibers and specialized intrafusal fibers, or muscle spindles, whose large IA afferents feed back to excite the alpha motor neuron via the neurotransmitter glutamate (44). In experimental settings, an excitatory input involving glutamate - such as from the spindle afferents - is necessary for certain excitotoxins to exert their deleterious effects (45, 46). Interestingly, motor neurons that lack a direct excitatory input from IA afferents are relatively spared in ALS. For example the motor neurons of nucleus X of Onuf serving the striated muscles of the external urethral and anal sphincters are spared (47, 48). These muscles consist of only slow-twitch fibers and lack muscle spindles (49). Motor neurons to eye muscles are also relatively spared in ALS. These muscles contain both fast and slow-twitch fibers as well as muscle spindles, but the IA afferents do not feed back onto the motor neuron (50). Interestingly, motor neurons serving the eye muscles and those arising from nucleus X of Onuf also lack direct cortical connections (51). Not only are motor neurons that lack direct input from muscle spindles relatively spared, but neurons other than motor neurons that receive input are affected. Thus degeneration of spinocerebellar neurons, which receive inputs from muscle spindles, has been demonstrated in patients with ALS (52). Conclusions
Given that the association between vigorous activity and ALS has been consistently found, fu-
147
VIGOROUS PHYSICAL ACTIVITY AND ALS
ture epidemiologic studies should seek to elucidate the specific mechanism that accounts for this association. Questions should include: intensity, estimated by caloric expenditure; setting, such as work place, indoor sport or outdoor sport; type, such as endurance versus power exercise; and the temporal relation of physical activity and disease onset. A greater understanding of the relation between vigorous physical activity and ALS may lead to a greater understanding of the cause and thus prevention of ALS. References
19.
20. 21, 22.
_+ L,.
1. Kurtzke JF. Epidemiology of amyotrophic 2.
3
4.
5.
6.
-l 8.
Y.
IO.
II.
12.
13.
13. 15. 16
17
lateral sclerosis. Adv Neural 36: 281, 1982. Yoshida S, Mulder DW, Kurland LT et al. Followup study on amyotrophic lateral sclerosis in Rochester, Mum., 1925 through 1984. Neuropidemiology 5: 61, 1986. Juergens SM, Kurland LT, Okasaki H, et al. Amyotrophic lateral sclerosis in Rochester, Minnesota, 1925 1977. Neurology 30: 463, 1980. Hansen S, Ballantyne JP. A quantitative electrophysiological study of motor neuron disease. J Neurol Neurosurg Psychiatry 41: 773, 1978. Spencer PS, Roy DN, Ludolph A, et. al. Lathrysm: evidence for role of the neuroexcitatory amino acid BOAA. Lancet 2: 1066, 1986. Spencer PS, Nunn PB, Hugon J, et. al. Guam ALSParkinsonism-Dementia linked to plant neurotoxin. Science 237: 517, 1987. Critchley M. Discussion on motor neurone disease. Proc R Sot Med 55: 1032, 1962. Rosati G, Pinna L, Granieri E, et. al. Studies on epidemiological, clinical and etiological aspects of ALS disease in Sardinia, southern Italy. Acta Neurol Stand 55: 231, 1977. Palo J, Jokelainen M. Geographic and social distribution of patients with amyotrophic lateral sclerosis. Arch Neurol 34: 724, 1977. Granieri E. Carreras M, Tola R, Paolino E, et. al. Motor neuron disease in the province of Ferrara, Italy in 1964- 1982. Neurology 38: 1604, 1988. Breland AE, Currier RD. Multiple sclerosis and amyotrophic lateral sclerosis in Mississippi. Neurology 17: 1011, 1967. Bracco L, Antuono P, Amaducci L. Study of epidemiological and etiological factors of amyotrophic lateral sclerosis in the province of Florence, Italy. Acta Neural Stand 60: 112, 1979. Gunnarsson LG, Palm R. Motor neuron disease and heavy manual labor: an epidemiologic study of Varmland county, Sweden. Neuroepidemiology 3: 195, 1984. Roelofs-Iverson RA, Mulder DW, Elveback LR, et. al. ALS and heavy metals: a pilot case-control study. Neurology 34: 393, 1984. Felmus MT, Patten BM, Swanke L. Antecedent events in amyotrophic lateral sclerosis. Neurology 26: 167, 1976. Currier RD, Conwill DE. Is amyotrophic lateral sclerosis caused by influenza and physical activity? Results of a twin study (abstract). Ann Neural 24: 148, 1988. Pierce-Ruhland R, Patten BM. Repeat studies of antecedent events in motor neuron disease. Ann Clin Res 13:
102, 1981.
1s. Kurtzke JF, Beebe GW. Epidemiology of amyotrophic
24.
25. 26.
27.
28. 29.
30.
31.
32.
33. 34.
35.
36.
37. 38. 39. 40.
lateral sclerosis: I. A case-control comparison based on ALS deaths. Neurology 30: 453, 1980. Campbell AMG. Williams ER, Barltrop D. Motor neuron disease and exposure to lead. J Neural Neurosurg Psychiatry 33: 877, 1970. Kondo K, Tsubaki T. Case-control studies of motor neuron disease: Association with mechanical injuries. Arch Neural 38: 220, 1981. Gawel A, Zaiwalla Z, Rose FC. Antecedent events in motor neuron disease. J Neurol Neurosurg Psychiatry 46: 1041, 1983. Gallagher JP, Sanders M. Trauma and ALS: A report of 78 patients. Acta Neurol Stand 75: 145, 1987. Patten BM, Mallette LE. Motor neuron disease: Retrospective study of associated abnormalities. Dis Nerv Sys 37: 318, 1976. Buckley J, Warlow C, Smith P, et. al. Motor neuron disease in England and Wales, 1959- 1979. J Neural Neurosurg psychiatry 46: 197, 1983. Hawkes CG, Fox AJ. Motor neuron disease in leather workers. Lancet 1: 507, 1981. Deapen DM, Henderson BE. A case-control study of amyotrophic lateral sclerosis. Am J Epidemiol 123: 790, 1986. Fimrite R. The battle of his life: Bob Waters is looking for answers to a deadly illness affecting former 49ers. Sports Illustrated 67: 72, 1987. Brayton CF. Dimethyl sulfoxide (DMSO): a review. Cornell Vet 76: 61, 1986. Weiner L. Possible role of androgen receptors in amyotrophic lateral sclerosis: a hypothesis. Arch Neural 37: 129, 1980. Sar M, Stumpf WE. Androgen concentration in motor neurons of cranial nerves and spinal cord. Science 197: 77, 1977. Decombaz J, Reinhardt P, Anantharaman K, van Glutz G, Poortmans JR. Biochemical changes in a 100 km run: free amino acids, urea and creatinine. Eur J Appl Physiol 41: 61, 1979. Oldendorf WH, Szabo J. Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Physiol 230: 94, 1976. Newsholme EA, Leech AR, eds. Biochemistry for the medical sciences. John Wiley and Sons, Chichester, 1983. Holstege JC, Kuypers HGJM. Brainstem projections to spinal motorneurons: an update. Neuroscience 23: 809, 1987. Plaitakis A, Smith J, Mandeli J, Yahr MD. Pilot trial of branched-chain amino acids in amyotrophic lateral sclerosis. Lancet 1: 1015, 1988. Price DL, Griffin J, Peck K. Tetanus toxin: evidence for binding at presynaptic nerve endings. Brain Res 121: 379, 1977. Price DL, Griffin J, Young A, et. al. Tetanus toxin: direct evidence for retrograde intraaxonal transport. Science 188: 945, 1975. Watson HD, Tignor GH, Smith AL. Entry of rabies virus into the peripheral nerves of mice. J Gen Viral 56: 371, 1981. Barauh JK, Rasool CG, Bradley WG, Munsat TL. Retrograde axonal transport of lead in rat sciatic nerve. Neurology 31: 612, 1981. Harrison PJ. Hultborn H, Jankowska E. Katz R, Storai
148
41.
42.
43. 44.
45.
46.
B, Zytnicki D. Labelling of interneurones by retrograde transsynaptic transport of horseradish peroxidase from motorneurones in rats and cats. Neurosci Lett 45: 15, 1984. Alstremark B, Kummel H. Transneuronal labelling of neurones projecting to forelimb motoneurones in cats performing different movements. Brain Res 376: 387, 1986. Iwasaki Y, Kinoshita M. Study on the relationship between the muscular pathology and prognosis in motor neuron disease. Jpn J Med 26: 335, 1987. Kandel ER. ed. Princioles of Neural Science. Elsevier/ North-Holland, New York, 1981. Mayer ML, Westbrook GL. Excitatory aminoacids: membrane physiology. p 125 in Neurotransmitter actions in the vertebrate nervous system. (Rogawski MA, Barker JL, eds) Plenum Press, New York, 1985. Ferkany JW, Zaczek R, Coyle JT. Kainic acid stimualtes excitatory amino acid neurotransmitter release at prersynaptic receptors. Nature 298: 757, 1982. Schwartz R, Foster AC, French ED, et. al. Excitotoxic models for neurodegenerative disorders. Life Sci 35: 19,
MEDICAL HYPOTHESES
1984. 47. Mannen T, Iwata M, Toyokura Y, et. al. Preservation of a certain motoneurone group of the sacral cord in amyotrophic lateral sclerosis: its clinical significance. J Neurol Neurosurg Psychiatry 40: 464, 1977. 48. Mannen T, Iwata M, Toyokura Y, et. al. The Onuf’s nucleus and the external anal sphincter muscles in amyotrophic lateral sclerosis and Shy-Drager syndrome. Acta Neuropathol 58: 255, 1982. 49. Gosling JA, Dixon JS, Critchley HOD, et. al. A comparative study of the human external sphincter and periurethral levator ani muscles. Br J Urol 53: 35, 1981. Williams 50. Miller NE, ed. Clinical neuro-ophthalmology. and Wilkins, Baltimore, 1985. 5 1. Iwatsubo T, Kuzuhara S, Kanemitsu A, Shimada H, Toyokura Y. Corticofugal projections to the motor nuclei of the brainstem and spinal cord in humans. Neurology 40,309, 1990. 52. Williams C, Kozlowski MA, Hinton DR, Miller CA. Degeneration of spinocerebellar neurons in amyotrophic lateral sclerosis. Ann Neural 27, 215, 1990.
Medical Hypotheses
MedicalUypofheses(1991) 34, 146148 0 Longman Group UK Ltd 1991
Hypotheses to Explain the Association Between Vigorous Physical Activity and Amyotrophic Lateral Sclerosis W.T. LONGSTRETH*t,
L.M. NELSON? T.D. KOEPSELL*
and G. VAN BELLE5
Neuroepidemiolog y Group, Division of Neurology, Department of Medicine, School of Medicine, ZA - 95, Harborview Medical Center, 325 Ninth Avenue, Seattle, WA 98 104 - 2499, USA. Departments of i Epidemiology, * Health Services, and 5 Biostatistics, School of Public Health and Community Medicine, University of Washington, Seattle, Washington, USA (Reprint requests to WTL) l
Abstract - Many epidemiologic studies indicate a relation between vigorous physical activity and amyotrophic lateral sclerosis. Physical activity itself is unlikely to cause amyotrophic lateral sclerosis, but could it modify the effects of other etiologic factors such as neurotoxins? Vigorous physical activity could potentiate the effect of a toxin to motor neurons by any of several mechanisms, especially if the toxin’s effects were mediated through excitation. Exercise could alter the extent of exposure or could influence the distribution, metabolism or potency of an excitotoxin. Future epidemiologic studies of amyotrophic lateral sclerosis should include sufficient detail about vigorous physical exercise to explore this relationship further.
Introduction Although amyotrophic lateral sclerosis (ALS) is rare, it is devastating. The reported incidence rates range from 0.5 - 2.4 per 100,000 persons per year (1) with a median survival of about two years (2). Rates increase with age and are greater in men than in women (3). A satisfactory treatment is lacking, and risk factors that can be modified have not been identified to guide efforts at prevention. Given that probably 50% or more of motor neurons are destroyed before a patient becomes symptomatic (4), treatments begun at such a late Date received Date accepted
stage may never hold much promise. Epidemiologic studies of risk factors are one approach to guide efforts at prevention. Some interplay among immutable host factors and modifiable environmental and behavioral factors likely determines who will develop ALS. This essay concentrates on vigorous physical activity, a risk factor that has been found consistently in epidemiologic studies of ALS. We know of no mechanism by which vigorous physical activity by itself could cause ALS, so we will seek an explanation for the association by hypothesizing how exercise could modify the effects of a neurotoxin that is
25 May 1990 15 August 1990
144
VIGOROUS
PHYSICAL
ACTIVITY
selective for motor neurons. Evidence is growing that ALS may be caused by exposure to a neurotoxin. Dietary neurotoxins have been proposed to cause lathyrism and Guamanian ALS, both human diseases of motor neurons. A constituent of chickling peas is associated with lathyrism (5), and of the cycad nut with Guamanian ALS (6). Both substances are analogs of alanine, mimic the actions of glutamate, and thus are classified as excitotoxins. In a 1962 conference on ALS, Critchley commented: ‘Nothing has been said about the possible role in aetiology of a previous habit of athleticism. I have the uncomfortable feeling that a past history of unnecessary muscular movement carried out for no obvious reason may be followed in later life by the development of motor neurone disease in a statistically significant number of cases’ (7). Well publicized cases of ALS in athletes, such as baseball’s Lou Gehrig, football’s Matt Hazeltine, boxing’s Ezzard Charles, and others, have also likely contributed to the concept of physical activity as a risk factor. Epidemiologic
evidence
In epidemiologic studies of ALS, vigorous physical activity during work (8 - 13) of leisure time (14, 15, 16) is an association that arises commonly. In the only incident case-control study (IO), the risk of ALS was increased among unskilled workers engaged in heavy labor (odds ratio = 2.0; 95% CI = 1.1 - 3.6). Breland and Currier (11) reported that 50% of men with ALS were heavy laborers in contrast to 30% of male control subjects (computed odds ratio = 2.4; 95% CI = 1.2-4.8). Other studies have reported that the incidence of ALS among heavy laborers is higher than expected based on the number of heavy laborers in the population (9, 12, 13). Felmus and associates (15) reported that ALS cases were significantly more likely to have a history of athletic participation than both healthy and diseased controls: 52% of patients with ALS earned major athletic awards or varsity letters compared with 24% of normal controls. Currier and Conwill (16) conducted a study of 17 twin pairs, one of whom had ALS. The affected member of each pair was more likely to have engaged in a life-long high level of physical activity which extended up to and past the onset of disease. Two studies failed to demonstrate an association between athletic activity and ALS (17, 18). In one (17), controls were childhood and adolescent friends who may have MH
(‘
145
AND ALS
been more likely to engage in the same activities as the cases and thus overmatching of cases and controls may have occurred. In the other (18), information on sports participation was missing for the majority of the cases and controls and thus could have compromised the power of the study. Several studies have identified physical trauma or limb injuries as risk factors for ALS (18-22), but failed to adjust in the analysis for vigorous physical activity, a factor that could predispose an individual to traumatic injury. Other reported risk factors that may also be associated with ALS by virtue of their relation to increased physical activity include male gender (1) and high levels of milk consumption (15, 17, 23). Other factors such as exposure to animal carcasses and hides (24, 25) and to electrical shock (21, 26) seem unrelated to physical activity. Hypotheses
Based on existing knowledge of the pathophysiology of ALS, it is intriguing to consider ways in which physical activity may affect the risk of ALS by modifying the extent or nature of the exposure to a neurotoxin or by influencing its distribution, metabolism or potency. One simple possibility is that an individual is exposed to the toxin during certain physical activities. A fertilizer applied to the playing field is one proposed explanation for why three professional football players from the San Francisco 49ers 1964 team developed ALS. Athletes are also exposed intentionally to other substances. For instance, players on this 1964 team commonly used dimethyl sulfoxide (DMSO) and anabolic steroids (27). DMSO is absorbed through the skin and increases transderma1 absorption of other compounds that would normally not enter the body by this route (28). The anabolic steroids are of note because of the possible importance of the androgens in ALS (29). Androgen receptors are found on those motor neurons that are commonly affected in ALS and are relatively sparse on motor neurons that are spared, such as those innervating the eye muscles (30). In addition to increasing the risk of exposure to a toxin, physical activity could potentiate the effects of the toxin by facilitating its transportation to its target. Vigorous physical activity could affect active transport systems across the bloodbrain barrier. Vigorous physical activity facilitates the uptake by muscle of branched-chain amino acids, namely leucine, isoleucine, and valine (31).
146 These same substances under usual circumstances would compete with other neutral amino acids for active transport across the blood-brain barrier. Glutamine, a potential precursor of glutamate, would also have less competition for transport across the blood-brain barrier during exercise (32). Thus, the potentially damaging effects of excessive glutamate could be increased. Enhanced transport of a hypothetical toxin, structurally or functionally similar to glutamate, could also occur. Tyrosine and tryptophan also compete for the same transport system and during exercise would have easier access to the central nervous system (33). These substances are precursors for the neurotransmitters catecholamine and serotonin, whose actions in descending tracts from the brain stem facilitate excitation of lower motor neurons (34). The actions of an excitotoxin could thus be potentiated. Interestingly, branched-chain amino acids have been proposed as a treatment for ALS and have shown promise in a preliminary randomized trial (35). They are thought to increase glutamate dehydrogenase and thus increase the breakdown of glutamate. If the toxin causing ALS were an analog of glutamate, then a similar beneficial effect of branched-chain amino acids could be expected. Instead of crossing the blood-brain barrier, the toxin could be taken up by the lower motor neuron’s axon and transported retrograde to the cell body, as occurs with the tetanus toxin (36, 37), rabies virus (38) and lead (39). Vigorous exercise that is associated with greater synaptic activity at the neuromuscular junction could cause more toxin to enter the distal axon. Greater synaptic acitivty leads to increased axonal transport (40, 41) that could result in greater amounts of toxin reaching the cell body. Besides these factors, physical activity may make the target cells more susceptible to injury from the toxin. At least one study suggested that motor neurons serving fast-twitch muscle fibers (Type II) were more susceptible in ALS than those to slow-twitch muscle fibers (Type I) (42). Perhaps the lower motor neurons that supply fast twitch fibers are more prone to injury because they fire at three times the rate of motor neurons that supply slow-twitch fibers (43). Physical activities that involve bursts of maximal muscle strength typically engage the fast-twitch fibers which are capable of dramatic hypertrophy; consider the physique of a weight lifter. In contrast, physical activities that involve endurance such as jogging, swimming,
MEDICAL HYPOTHESES
and cycling result in more slow-twitch fiber activity. These fibers have limited capacity for hypertrophy, explaining why marathon runners typically lack the change in physique seen in power athletes. In someone who is sedentary, the fasttwitch fibers may never be activated because the slow-twitch fibers are activated first and may be all that is needed for sedentary activities. If physical activity, especially that involving fast-twitch fibers, is an important factor in developing ALS, then a sedentary person may be relatively resistant to ALS and would require a high dose of exposure to the toxin to develop ALS. Endurance athletes may be more susceptible, but not as susceptible as power athletes. Increased discharges from muscle spindle afferents during vigorous physical activity may also potentiate the effects of a toxin. A typical limb muscle contains a mixture of the usual extrafusal fibers and specialized intrafusal fibers, or muscle spindles, whose large IA afferents feed back to excite the alpha motor neuron via the neurotransmitter glutamate (44). In experimental settings, an excitatory input involving glutamate - such as from the spindle afferents - is necessary for certain excitotoxins to exert their deleterious effects (45, 46). Interestingly, motor neurons that lack a direct excitatory input from IA afferents are relatively spared in ALS. For example the motor neurons of nucleus X of Onuf serving the striated muscles of the external urethral and anal sphincters are spared (47, 48). These muscles consist of only slow-twitch fibers and lack muscle spindles (49). Motor neurons to eye muscles are also relatively spared in ALS. These muscles contain both fast and slow-twitch fibers as well as muscle spindles, but the IA afferents do not feed back onto the motor neuron (50). Interestingly, motor neurons serving the eye muscles and those arising from nucleus X of Onuf also lack direct cortical connections (51). Not only are motor neurons that lack direct input from muscle spindles relatively spared, but neurons other than motor neurons that receive input are affected. Thus degeneration of spinocerebellar neurons, which receive inputs from muscle spindles, has been demonstrated in patients with ALS (52). Conclusions
Given that the association between vigorous activity and ALS has been consistently found, fu-
147
VIGOROUS PHYSICAL ACTIVITY AND ALS
ture epidemiologic studies should seek to elucidate the specific mechanism that accounts for this association. Questions should include: intensity, estimated by caloric expenditure; setting, such as work place, indoor sport or outdoor sport; type, such as endurance versus power exercise; and the temporal relation of physical activity and disease onset. A greater understanding of the relation between vigorous physical activity and ALS may lead to a greater understanding of the cause and thus prevention of ALS. References
19.
20. 21, 22.
_+ L,.
1. Kurtzke JF. Epidemiology of amyotrophic 2.
3
4.
5.
6.
-l 8.
Y.
IO.
II.
12.
13.
13. 15. 16
17
lateral sclerosis. Adv Neural 36: 281, 1982. Yoshida S, Mulder DW, Kurland LT et al. Followup study on amyotrophic lateral sclerosis in Rochester, Mum., 1925 through 1984. Neuropidemiology 5: 61, 1986. Juergens SM, Kurland LT, Okasaki H, et al. Amyotrophic lateral sclerosis in Rochester, Minnesota, 1925 1977. Neurology 30: 463, 1980. Hansen S, Ballantyne JP. A quantitative electrophysiological study of motor neuron disease. J Neurol Neurosurg Psychiatry 41: 773, 1978. Spencer PS, Roy DN, Ludolph A, et. al. Lathrysm: evidence for role of the neuroexcitatory amino acid BOAA. Lancet 2: 1066, 1986. Spencer PS, Nunn PB, Hugon J, et. al. Guam ALSParkinsonism-Dementia linked to plant neurotoxin. Science 237: 517, 1987. Critchley M. Discussion on motor neurone disease. Proc R Sot Med 55: 1032, 1962. Rosati G, Pinna L, Granieri E, et. al. Studies on epidemiological, clinical and etiological aspects of ALS disease in Sardinia, southern Italy. Acta Neurol Stand 55: 231, 1977. Palo J, Jokelainen M. Geographic and social distribution of patients with amyotrophic lateral sclerosis. Arch Neurol 34: 724, 1977. Granieri E. Carreras M, Tola R, Paolino E, et. al. Motor neuron disease in the province of Ferrara, Italy in 1964- 1982. Neurology 38: 1604, 1988. Breland AE, Currier RD. Multiple sclerosis and amyotrophic lateral sclerosis in Mississippi. Neurology 17: 1011, 1967. Bracco L, Antuono P, Amaducci L. Study of epidemiological and etiological factors of amyotrophic lateral sclerosis in the province of Florence, Italy. Acta Neural Stand 60: 112, 1979. Gunnarsson LG, Palm R. Motor neuron disease and heavy manual labor: an epidemiologic study of Varmland county, Sweden. Neuroepidemiology 3: 195, 1984. Roelofs-Iverson RA, Mulder DW, Elveback LR, et. al. ALS and heavy metals: a pilot case-control study. Neurology 34: 393, 1984. Felmus MT, Patten BM, Swanke L. Antecedent events in amyotrophic lateral sclerosis. Neurology 26: 167, 1976. Currier RD, Conwill DE. Is amyotrophic lateral sclerosis caused by influenza and physical activity? Results of a twin study (abstract). Ann Neural 24: 148, 1988. Pierce-Ruhland R, Patten BM. Repeat studies of antecedent events in motor neuron disease. Ann Clin Res 13:
102, 1981.
1s. Kurtzke JF, Beebe GW. Epidemiology of amyotrophic
24.
25. 26.
27.
28. 29.
30.
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