Amyotrophic lateral sclerosis (ALS) is characterized by selective and progressive degeneration of motoneurons (MNs). Although the etiology of the disease is unknown, glutamate toxicity and reactive oxygen species toxicity have been strongly implicated in ALS pathophysiology, Training exercise has been proposed to provide a beneficial therapy during the early or late stages of ALS; however, some studies showed deleterious effects of exercise on survival in ALS

ElBasiouny, Sherif M.

Schuster, Jenna E.

English

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Elbasiouny, Sherif M.

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Wright State University CORE Scholar Neuroscience, Cell Biology & Physiology Faculty Publications Neuroscience, Cell Biology & Physiology 4-25-2011 The Effect of Training on Motoneuron Survival in Amyotrophic Lateral Sclerosis: Which Motoneuron Type is Saved? Sherif M. Elbasiouny Wright State University - Main Campus, sherif.elbasiouny@wright.edu Jenna E. Schuster Follow this and additional works at: https://corescholar.libraries.wright.edu/ncbp  Part of the Medical Cell Biology Commons, Medical Neurobiology Commons, Medical Physiology Commons, Neurosciences Commons, and the Physiological Processes Commons Repository Citation Elbasiouny, S. M., & Schuster, J. E. (2011). The Effect of Training on Motoneuron Survival in Amyotrophic Lateral Sclerosis: Which Motoneuron Type is Saved?. Frontiers in Psychology, 2, 18. https://corescholar.libraries.wright.edu/ncbp/1101 This Article is brought to you for free and open access by the Neuroscience, Cell Biology & Physiology at CORE Scholar. It has been accepted for inclusion in Neuroscience, Cell Biology & Physiology Faculty Publications by an authorized administrator of CORE Scholar. For more information, please contact library-corescholar@wright.edu. www.frontiersin.org April 2011 | Volume 2 | Article 18 | 1OpiniOn Articlepublished: 25 April 2011doi: 10.3389/fphys.2011.00018The effect of training on motoneuron survival in amyotrophic lateral sclerosis: which motoneuron type is saved?Sherif M. ElBasiouny* and Jenna E. SchusterHeckman Lab, Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA*Correspondence: s-elbasiouny@northwestern.eduAmyotrophic lateral sclerosis (ALS) is  characterized by selective and progres-sive degeneration of motoneurons (MNs). Although the etiology of the disease is unknown, glutamate toxicity and reac-tive oxygen species toxicity have been strongly implicated in ALS pathophysiol-ogy, Training exercise has been proposed to provide a beneficial therapy during the early or late stages of ALS (Pinto et al., 1999; Drory et al., 2001); however, some studies showed deleterious effects of exercise on survival in ALS (Mahoney et al., 2004). The beneficial effects are based on the cellular adaptations induced by training exercise in the brain, spinal cord, and skeletal muscles that could counteract the oxidative stress complication in ALS. For instance, training exercise increases the capacity of antioxi-dant enzymes and reduces lipid perox-ides in brain regions of rats (Somani and Husain, 1997; Husain and Somani, 1998). In skeletal muscle, training reduces oxidative stress following exercise (Miyazaki et al., 2001), increases the mitochondrial capac-ity (Holloszy et al., 1970), and increases the expression of neurotrophic factors (Gomez-Pinilla et al., 2001). The latter could be particularly beneficial in ALS because neurotrophic factors could prevent MN degeneration, preserve muscle inner-vation, and inhibit muscle atrophy (Acsadi et al., 2002; Manabe et al., 2002; Sun et al., 2002). Therefore, it is conceivable that train-ing exercise could be beneficial by resisting oxidative stress and offsetting energy defi-cits caused by mitochondrial dysfunction in ALS. In a recent study, training exercise has been also shown to have neuroprotec-tive effects in the spinal cord by saving MNs from degeneration, in addition to maintain-ing muscle fiber composition (Deforges et al., 2009). The Deforges et al. (2009) study is important for understanding the effect of training exercise in ALS because it compared two training paradigms and showed differential neuroprotective effects in the spinal cord. Here we discuss the methodology and interpretation from the Deforges et al. (2009) study on which MN type is saved by training exercise, and try to reconcile their conclusions with the litera-ture and more recent work.Deforges et al. (2009) examined the effect of two training exercise paradigms (i.e., running and swimming) on MN survival and muscle fiber composition in the G93A (high expressor line) mouse model of ALS. In comparison to other ALS mouse models, this model has high level of expression of the mutant human SOD1 gene, rapid disease onset, and short life span. Training exer-cise was performed through 30 min daily running or swimming sessions that started at postnatal day 70 (P70) and lasted until P115 or death. Mice survival, MN count, and muscle fiber composition were assessed at P115 in the fast twitch muscles tibialis and plantaris and the slow twitch soleus muscle of the G93A mouse groups (i.e., running and swimming ALS groups), and were compared to normal, non- transgenic (control group), and untrained G93A trans-genic mice (sedentary ALS group). MN count was based on soma cross-sectional area in which MNs were classified into three types: small (soma size <300 μm2), medium (soma size 300–700 μm2), and large (soma size >700 μm2) soma MN types. Muscle fiber composition was examined using immun-ofluorescence in which muscle fibers were incubated with antibodies raised against myosin heavy chains (MyHC) for slow (type I) and fast (types II, IIa, and IIb) fibers. The percentage of fast fiber type IIx was deter-mined as the difference between the number of type II fibers and the sum of type IIa and IIb fibers [IIx = II − (IIb + IIa)]. The results showed that in the sedentary ALS group the disease caused MN loss in the ventral horn of 49% relative to control with a reduction in the proportion of medium and large MN types and increase in the proportion of small MN type. In fast twitch muscles, the disease caused a significant transition in muscle fiber types from fast-to-slow (type II to type I) and within the type II fiber type (from type IIb/IIx to type IIa). The slow twitch soleus muscle, on the other hand, experienced an increase in the proportion of type IIx muscle fibers. The G93A trans-genic mice in the running ALS group did not have significant difference in symptom onset or survival time and had comparable loss of MNs (45%) to the sedentary group. In contrast, the G93A transgenic mice in the swimming ALS group survived longer and had delayed symptom onset relative to the sedentary ALS group. They also had higher MN total number and higher proportion of medium-size MNs relative to the sed-entary ALS group, and maintained muscle fiber composition in all muscles similar to the control group. The authors concluded that swimming preferentially activated large MNs, innervating fast muscle fibers of type II), and protected them.On their methodology, Deforges et al. (2009) measured the number of surviving MNs by counting MN cell bodies in the ven-tral horn of spinal cord. Although this pro-vides anatomical evidence, this technique does not provide information on the func-tional state of MNs (i.e., whether surviving MNs produce muscle contractions). This is exceptionally important in ALS because MNs retract from the neuromuscular junc-tion before the MN cell body dies (Fischer et al., 2004). Second, Deforges et al. (2009) classified MNs based on their morphologi-cal properties (e.g., soma size). This method could be misleading in ALS because WT and mutant MNs exhibit differences in morphology and cell size (Amendola and Durand, 2008) and, for all mice, the sepa-ration between MN types based on soma size is problematic because there is a con-tinuum of sizes (McHanwell and Biscoe, 1981). To avoid these problems, functional motor unit electrophysiology, in which the number of surviving MNs is estimated from isometric whole muscle and single motor unit twitch forces (Gordon et al., 2010), could be used together with MN cell body Frontiers in Physiology | Exercise Physiology  April 2011 | Volume 2 | Article 18 | 2ElBasiouny and Schuster Effect of training in ALSAmendola, J., and Durand, J. (2008). Morphological  differences between wild-type and transgenic super-oxide dismutase 1 lumbar motoneurons in postnatal mice. J. Comp. Neurol. 511, 329–341.Bories, C., Amendola, J., Lamotte d’Incamps, B., and Durand, J. (2007). Early electrophysiological abnor-malities in lumbar motoneurons in a transgenic mouse model of amyotrophic lateral sclerosis. Eur. J. Neurosci. 25, 451–459.Clément, G., Olivier, B., Claude, P., Philippe, L., Séverine, D., Sylvie, L., Bruno Della, G., Claude-Louis, G., Christophe, C., and Frédéric, C. (2008). Exercise-induced modulation of calcineurin activity parallels the time course of myofibre transitions. J. Cell. Physiol. 214, 126–135.Deforges, S., Branchu, J., Biondi, O., Grondard, C., Pariset, C., Lecolle, S., Lopes, P., Vidal, P. P., Chanoine, C., and Charbonnier, F. (2009). Motoneuron sur-vival is promoted by specific exercise in a mouse model of amyotrophic lateral sclerosis. J. Physiol. 587, 3561–3572.Drory, V. E., Goltsman, E., Reznik, J. G., Mosek, A., and Korczyn, A. D. (2001). The value of muscle exercise in patients with amyotrophic lateral sclerosis. J. Neurol. Sci. 191, 133–137.Fischer, L. R., Culver, D. G., Tennant, P., Davis, A. A., Wang, M., Castellano-Sanchez, A., Khan, J., Polak, M. A., and Glass, J. D. (2004). Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp. Neurol. 185, 232–240.Gomez-Pinilla, F., Ying, Z., Opazo, P., Roy, R. R., and Edgerton, V. R. (2001). Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle. Eur. J. Neurosci. 13, 1078–1084.Gordon, T., Tyreman, N., Li, S., Putman, C. T., and Hegedus, J. (2010). Functional over-load saves motor units in the SOD1-G93A transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis. 37, 412–422.Holloszy, J. O., Oscai, L. B., Don, I. J., and Mole, P. A. (1970). Mitochondrial citric acid cycle and related enzymes: adaptive response to exercise. Biochem. Biophys. Res. Commun. 40, 1368–1373.Husain, K., and Somani, S. M. (1998). Effect of exercise training and chronic ethanol ingestion on cholineste-rase activity and lipid peroxidation in blood and brain regions of rat. Prog. Neuropsychopharmacol. Biol. Psychiatry 22, 411–423.Ishihara, A., Ohira, Y., Tanaka, M., Nishikawa, W., Ishioka, N., Higashibata, A., Izumi, R., Shimazu, T., and Ibata, Y. (2001). Cell body size and succinate dehydrogenase activity of spinal motoneurons innervating the soleus muscle in mice, rats, and cats. Neurochem. Res. 26, 1301–1304.Mahoney, D. J., Rodriguez, C., Devries, M., Yasuda, N., and Tarnopolsky, M. A. (2004). Effects of high- intensity endurance exercise training in the G93A mouse model of amyotrophic lateral sclerosis. Muscle Nerve 29, 656–662.Manabe, Y., Nagano, I., Gazi, M. S., Murakami, T., Shiote, M., Shoji, M., Kitagawa, H., Setoguchi, Y., and Abe, K. (2002). Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor prevents motor neuron loss of transgenic model mice for amyotrophic lateral sclerosis. Apoptosis 7, 329–334.McHanwell, S., and Biscoe, T. J. (1981). The sizes of motoneurons supplying hindlimb muscles in the mouse. Proc. R. Soc. Lond. B Biol. Sci. 213, 201–216.motor units, which are innervated by the small alpha-MNs. This conversion was supported by both  electrophysiological recordings and histochemical staining techniques.In Deforges et al. (2009), a fundamental concept the authors claimed is that swim-ming exercise preferentially recruits the larger, faster motor units in contrast to the running exercise that recruits the smaller, slower motor units. Certainly, recruitment is orderly from small to large motor units although the relative recruitment of large motor units may differ with the exercise. In other words, swimming exercise must have involved activation of both small and large MNs, whereas running exercise involved mainly activation of small MNs, with maybe some activation of large MNs. With that in mind, the beneficial effect of swimming, but not running, exercise on MN survival in ALS could be explained in the context of their electrical properties. In the neonatal phase, large mutant MNs are vulnerable and selectively exhibit 30% reduction in their input resistance relative to WT (Bories et al., 2007), which makes them harder to recruit. Therefore, exercise of sufficient intensity to activate large MNs, such as swimming exer-cise as in the Deforges et al. (2009) study or functional overload of spared motor units as in the Gordon et al. (2010) study, could then be essential to both recruit and convert them to slow MNs. Also, specific types of synaptic inputs to MNs are lost in ALS [e.g., choliner-gic synapses on MNs are lost in ALS as shown by Nagao et al. (1998)] and it is possible that training exercise rescues vulnerable MNs in part by strengthening remaining inputs to MNs. These are open questions that warrant further investigations.AcknowledgmentsSherif M. ElBasiouny was supported by the Tim E. Noel fellowship from the ALS Society of Canada and the Canadian Institutes of Health Research (CIHR). Jenna E. Schuster was supported by the National Institutes of Health (NIH).RefeRencesAcsadi, G., Anguelov, R. A., Yang, H., Toth, G., Thomas, R., Jani, A., Wang, Y., Ianakova, E., Mohammad, S., Lewis, R. A., and Shy, M. E. (2002). Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy. Hum. Gene Ther. 13, 1047–1059.count to measure the number of functional surviving MNs. Although conducting func-tional motor unit electrophysiology would add complexity to the experiment, it would also allow for distinguishing between motor unit types (fast vs. slow) accurately based on their contractile properties.Regarding their interpretation, the authors in Deforges et al. (2009) concluded from their soma size measurements that swimming rescued large MNs and saved them from degeneration. However, in their MN classification the authors did not consider gamma-MNs, which have the smallest soma size in the ventral horn of the spinal cord. With that in mind, the results of the Deforges et al. (2009) could be reinterpreted in light of published liter-ature on the soma size of various MN types in adult WT mice. Accordingly, MNs that were saved by swimming exercise (whose soma size is between 300 and 700 μm2) actually correspond to small alpha-MNs (whose soma size ranges between 450 and 580 μm2; McHanwell and Biscoe, 1981; Ishihara et al., 2001), which innervate slow muscle fibers. Also, MNs that were reduced in proportion by swimming exer-cise (whose soma size is <300 μm2) actually correspond to gamma-MNs (whose soma size ranges between 200 and 250 μm2; McHanwell and Biscoe, 1981; Ishihara et al., 2001), which are spared in the disease (Sobue et al., 1981). Moreover, the propor-tion of large alpha-MNs (whose soma size is >700 μm2), which innervate fast muscle fibers, did not change with swimming, indicating that “true” large MNs were not protected. In sum, swimming exercise actually increased the proportion of small alpha-MNs, which innervate slow muscle fibers, even if large MNs were preferentially activated as claimed by the authors. This effect could be due to MN conversion from the large to small type by the effect of the training exercise. This reinterpretation is also consistent with a previous study in which swimming training in normal (i.e., non-transgenic) mice was shown to induce a fast-to-slow fiber conversion (Clément et al., 2008). In light of this reinterpreta-tion, the Deforges et al. (2009) comes in agreement with Gordon et al. (2010) in which increased neuromuscular activ-ity in G93A transgenic mice saved fast motor units by converting them to slow www.frontiersin.org April 2011 | Volume 2 | Article 18 | 3ElBasiouny and Schuster Effect of training in ALSReceived: 22 March 2011; accepted: 12 April 2011; published online: 25 April 2011.Citation: ElBasiouny SM and Schuster JE (2011) The effect of training on motoneuron survival in amyotrophic lateral sclerosis: which motoneuron type is saved? Front. Physio. 2:18. doi: 10.3389/fphys.2011.00018This article was submitted to Frontiers in Exercise Physiology, a specialty of Frontiers in Physiology.Copyright © 2011 ElBasiouny and Schuster. This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, dis-tribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.Sobue, G., Matsuoka, Y., Mukai, E., Takayanagi, T., Sobue, I., and Hashizume, Y. (1981). Spinal and  cranial motor nerve roots in amyotrophic lateral sclerosis and X-linked recessive bulbospinal muscular atro-phy: morphometric and teased-fiber study. Acta Neuropathol. 55, 227–235.Somani, S. M., and Husain, K. (1997). Interaction of exer-cise training and chronic ethanol ingestion on anti-oxidant system of rat brain regions. J. Appl. Toxicol. 17, 329–336.Sun, W., Funakoshi, H., and Nakamura, T. (2002). Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS. J. Neurosci. 22, 6537–6548.Miyazaki, H., Oh-Ishi, S., Ookawara, T., Kizaki, T., Toshinai, K., Ha, S., Haga, S., Ji, L. L., and Ohno, H. (2001). Strenuous endurance training in humans reduces oxidative stress following exhausting exercise. Eur. J. Appl. Physiol. 84, 1–6.Nagao, M., Misawa, H., Kato, S., and Hirai, S. (1998). Loss of cholinergic synapses on the spinal motor neurons of amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 57, 329–333.Pinto, A. C., Alves, M., Nogueira, A., Evangelista, T., Carvalho, J., Coelho, A., de Carvalho, M., and Sales-Luis, M. L. (1999). Can amyotrophic lateral sclerosis patients with respiratory insufficiency exercise? J. Neurol. Sci. 169, 69–75.

The Effect of Training on Motoneuron Survival in Amyotrophic Lateral Sclerosis: Which Motoneuron Type is Saved?

Sherif M. ElBasiouny

Jenna E. Schuster

Crossref

Frontiers in Physiology

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www.frontiersin.org April 2011 | Volume 2 | Article 18 | 1
OpiniOn Article
published: 25 April 2011
doi: 10.3389/fphys.2011.00018
The effect of training on motoneuron survival in amyotrophic 
lateral sclerosis: which motoneuron type is saved?
Sherif M. ElBasiouny* and Jenna E. Schuster
Heckman Lab, Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
*Correspondence: s-elbasiouny@northwestern.edu
Amyotrophic lateral sclerosis (ALS) is 
 characterized by selective and progres-
sive degeneration of motoneurons (MNs). 
Although the etiology of the disease is 
unknown, glutamate toxicity and reac-
tive oxygen species toxicity have been 
strongly implicated in ALS pathophysiol-
ogy, Training exercise has been proposed 
to provide a beneficial therapy during the 
early or late stages of ALS (Pinto et al., 1999; 
Drory et al., 2001); however, some studies 
showed deleterious effects of exercise on 
survival in ALS (Mahoney et al., 2004). The 
beneficial effects are based on the cellular 
adaptations induced by training exercise in 
the brain, spinal cord, and skeletal muscles 
that could counteract the oxidative stress 
complication in ALS. For instance, training 
exercise increases the capacity of antioxi-
dant enzymes and reduces lipid perox-
ides in brain regions of rats (Somani and 
Husain, 1997; Husain and Somani, 1998). In 
skeletal muscle, training reduces oxidative 
stress following exercise (Miyazaki et al., 
2001), increases the mitochondrial capac-
ity (Holloszy et al., 1970), and increases 
the expression of neurotrophic factors 
(Gomez-Pinilla et al., 2001). The latter 
could be particularly beneficial in ALS 
because neurotrophic factors could prevent 
MN degeneration, preserve muscle inner-
vation, and inhibit muscle atrophy (Acsadi 
et al., 2002; Manabe et al., 2002; Sun et al., 
2002). Therefore, it is conceivable that train-
ing exercise could be beneficial by resisting 
oxidative stress and offsetting energy defi-
cits caused by mitochondrial dysfunction 
in ALS. In a recent study, training exercise 
has been also shown to have neuroprotec-
tive effects in the spinal cord by saving MNs 
from degeneration, in addition to maintain-
ing muscle fiber composition (Deforges 
et al., 2009). The Deforges et al. (2009) 
study is important for understanding the 
effect of training exercise in ALS because 
it compared two training paradigms and 
showed differential neuroprotective effects 
in the spinal cord. Here we discuss the 
methodology and interpretation from the 
Deforges et al. (2009) study on which MN 
type is saved by training exercise, and try to 
reconcile their conclusions with the litera-
ture and more recent work.
Deforges et al. (2009) examined the effect 
of two training exercise paradigms (i.e., 
running and swimming) on MN survival 
and muscle fiber composition in the G93A 
(high expressor line) mouse model of ALS. 
In comparison to other ALS mouse models, 
this model has high level of expression of the 
mutant human SOD1 gene, rapid disease 
onset, and short life span. Training exer-
cise was performed through 30 min daily 
running or swimming sessions that started 
at postnatal day 70 (P70) and lasted until 
P115 or death. Mice survival, MN count, 
and muscle fiber composition were assessed 
at P115 in the fast twitch muscles tibialis 
and plantaris and the slow twitch soleus 
muscle of the G93A mouse groups (i.e., 
running and swimming ALS groups), and 
were compared to normal, non- transgenic 
(control group), and untrained G93A trans-
genic mice (sedentary ALS group). MN 
count was based on soma cross-sectional 
area in which MNs were classified into three 
types: small (soma size <300 μm2), medium 
(soma size 300–700 μm2), and large (soma 
size >700 μm2) soma MN types. Muscle fiber 
composition was examined using immun-
ofluorescence in which muscle fibers were 
incubated with antibodies raised against 
myosin heavy chains (MyHC) for slow (type 
I) and fast (types II, IIa, and IIb) fibers. The 
percentage of fast fiber type IIx was deter-
mined as the difference between the number 
of type II fibers and the sum of type IIa and 
IIb fibers [IIx = II − (IIb + IIa)]. The results 
showed that in the sedentary ALS group the 
disease caused MN loss in the ventral horn 
of 49% relative to control with a reduction 
in the proportion of medium and large 
MN types and increase in the proportion 
of small MN type. In fast twitch muscles, 
the disease caused a significant transition in 
muscle fiber types from fast-to-slow (type II 
to type I) and within the type II fiber type 
(from type IIb/IIx to type IIa). The slow 
twitch soleus muscle, on the other hand, 
experienced an increase in the proportion 
of type IIx muscle fibers. The G93A trans-
genic mice in the running ALS group did 
not have significant difference in symptom 
onset or survival time and had comparable 
loss of MNs (45%) to the sedentary group. 
In contrast, the G93A transgenic mice in the 
swimming ALS group survived longer and 
had delayed symptom onset relative to the 
sedentary ALS group. They also had higher 
MN total number and higher proportion 
of medium-size MNs relative to the sed-
entary ALS group, and maintained muscle 
fiber composition in all muscles similar to 
the control group. The authors concluded 
that swimming preferentially activated large 
MNs, innervating fast muscle fibers of type 
II), and protected them.
On their methodology, Deforges et al. 
(2009) measured the number of surviving 
MNs by counting MN cell bodies in the ven-
tral horn of spinal cord. Although this pro-
vides anatomical evidence, this technique 
does not provide information on the func-
tional state of MNs (i.e., whether surviving 
MNs produce muscle contractions). This 
is exceptionally important in ALS because 
MNs retract from the neuromuscular junc-
tion before the MN cell body dies (Fischer 
et al., 2004). Second, Deforges et al. (2009) 
classified MNs based on their morphologi-
cal properties (e.g., soma size). This method 
could be misleading in ALS because WT 
and mutant MNs exhibit differences in 
morphology and cell size (Amendola and 
Durand, 2008) and, for all mice, the sepa-
ration between MN types based on soma 
size is problematic because there is a con-
tinuum of sizes (McHanwell and Biscoe, 
1981). To avoid these problems, functional 
motor unit electrophysiology, in which the 
number of surviving MNs is estimated from 
isometric whole muscle and single motor 
unit twitch forces (Gordon et al., 2010), 
could be used together with MN cell body 
Frontiers in Physiology | Exercise Physiology  April 2011 | Volume 2 | Article 18 | 2
ElBasiouny and Schuster Effect of training in ALS
Amendola, J., and Durand, J. (2008). Morphological 
 differences between wild-type and transgenic super-
oxide dismutase 1 lumbar motoneurons in postnatal 
mice. J. Comp. Neurol. 511, 329–341.
Bories, C., Amendola, J., Lamotte d’Incamps, B., and 
Durand, J. (2007). Early electrophysiological abnor-
malities in lumbar motoneurons in a transgenic 
mouse model of amyotrophic lateral sclerosis. Eur. 
J. Neurosci. 25, 451–459.
Clément, G., Olivier, B., Claude, P., Philippe, L., Séverine, 
D., Sylvie, L., Bruno Della, G., Claude-Louis, G., 
Christophe, C., and Frédéric, C. (2008). Exercise-
induced modulation of calcineurin activity parallels 
the time course of myofibre transitions. J. Cell. Physiol. 
214, 126–135.
Deforges, S., Branchu, J., Biondi, O., Grondard, C., 
Pariset, C., Lecolle, S., Lopes, P., Vidal, P. P., Chanoine, 
C., and Charbonnier, F. (2009). Motoneuron sur-
vival is promoted by specific exercise in a mouse 
model of amyotrophic lateral sclerosis. J. Physiol. 
587, 3561–3572.
Drory, V. E., Goltsman, E., Reznik, J. G., Mosek, A., and 
Korczyn, A. D. (2001). The value of muscle exercise in 
patients with amyotrophic lateral sclerosis. J. Neurol. 
Sci. 191, 133–137.
Fischer, L. R., Culver, D. G., Tennant, P., Davis, A. A., Wang, 
M., Castellano-Sanchez, A., Khan, J., Polak, M. A., and 
Glass, J. D. (2004). Amyotrophic lateral sclerosis is a 
distal axonopathy: evidence in mice and man. Exp. 
Neurol. 185, 232–240.
Gomez-Pinilla, F., Ying, Z., Opazo, P., Roy, R. R., and 
Edgerton, V. R. (2001). Differential regulation by 
exercise of BDNF and NT-3 in rat spinal cord and 
skeletal muscle. Eur. J. Neurosci. 13, 1078–1084.
Gordon, T., Tyreman, N., Li, S., Putman, C. T., and 
Hegedus, J. (2010). Functional over-load saves motor 
units in the SOD1-G93A transgenic mouse model 
of amyotrophic lateral sclerosis. Neurobiol. Dis. 37, 
412–422.
Holloszy, J. O., Oscai, L. B., Don, I. J., and Mole, P. A. 
(1970). Mitochondrial citric acid cycle and related 
enzymes: adaptive response to exercise. Biochem. 
Biophys. Res. Commun. 40, 1368–1373.
Husain, K., and Somani, S. M. (1998). Effect of exercise 
training and chronic ethanol ingestion on cholineste-
rase activity and lipid peroxidation in blood and brain 
regions of rat. Prog. Neuropsychopharmacol. Biol. 
Psychiatry 22, 411–423.
Ishihara, A., Ohira, Y., Tanaka, M., Nishikawa, W., Ishioka, 
N., Higashibata, A., Izumi, R., Shimazu, T., and Ibata, 
Y. (2001). Cell body size and succinate dehydrogenase 
activity of spinal motoneurons innervating the soleus 
muscle in mice, rats, and cats. Neurochem. Res. 26, 
1301–1304.
Mahoney, D. J., Rodriguez, C., Devries, M., Yasuda, N., and 
Tarnopolsky, M. A. (2004). Effects of high- intensity 
endurance exercise training in the G93A mouse 
model of amyotrophic lateral sclerosis. Muscle Nerve 
29, 656–662.
Manabe, Y., Nagano, I., Gazi, M. S., Murakami, T., Shiote, 
M., Shoji, M., Kitagawa, H., Setoguchi, Y., and Abe, 
K. (2002). Adenovirus-mediated gene transfer of glial 
cell line-derived neurotrophic factor prevents motor 
neuron loss of transgenic model mice for amyotrophic 
lateral sclerosis. Apoptosis 7, 329–334.
McHanwell, S., and Biscoe, T. J. (1981). The sizes of 
motoneurons supplying hindlimb muscles in the 
mouse. Proc. R. Soc. Lond. B Biol. Sci. 213, 201–216.
motor units, which are innervated by the 
small alpha-MNs. This conversion was 
supported by both  electrophysiological 
recordings and histochemical staining 
techniques.
In Deforges et al. (2009), a fundamental 
concept the authors claimed is that swim-
ming exercise preferentially recruits the 
larger, faster motor units in contrast to the 
running exercise that recruits the smaller, 
slower motor units. Certainly, recruitment 
is orderly from small to large motor units 
although the relative recruitment of large 
motor units may differ with the exercise. In 
other words, swimming exercise must have 
involved activation of both small and large 
MNs, whereas running exercise involved 
mainly activation of small MNs, with maybe 
some activation of large MNs. With that in 
mind, the beneficial effect of swimming, 
but not running, exercise on MN survival 
in ALS could be explained in the context of 
their electrical properties. In the neonatal 
phase, large mutant MNs are vulnerable 
and selectively exhibit 30% reduction in their 
input resistance relative to WT (Bories et al., 
2007), which makes them harder to recruit. 
Therefore, exercise of sufficient intensity to 
activate large MNs, such as swimming exer-
cise as in the Deforges et al. (2009) study or 
functional overload of spared motor units as 
in the Gordon et al. (2010) study, could then 
be essential to both recruit and convert them 
to slow MNs. Also, specific types of synaptic 
inputs to MNs are lost in ALS [e.g., choliner-
gic synapses on MNs are lost in ALS as shown 
by Nagao et al. (1998)] and it is possible that 
training exercise rescues vulnerable MNs in 
part by strengthening remaining inputs to 
MNs. These are open questions that warrant 
further investigations.
Acknowledgments
Sherif M. ElBasiouny was supported by the 
Tim E. Noel fellowship from the ALS Society 
of Canada and the Canadian Institutes of 
Health Research (CIHR). Jenna E. Schuster 
was supported by the National Institutes of 
Health (NIH).
RefeRences
Acsadi, G., Anguelov, R. A., Yang, H., Toth, G., Thomas, 
R., Jani, A., Wang, Y., Ianakova, E., Mohammad, S., 
Lewis, R. A., and Shy, M. E. (2002). Increased survival 
and function of SOD1 mice after glial cell-derived 
neurotrophic factor gene therapy. Hum. Gene Ther. 
13, 1047–1059.
count to measure the number of functional 
surviving MNs. Although conducting func-
tional motor unit electrophysiology would 
add complexity to the experiment, it would 
also allow for distinguishing between motor 
unit types (fast vs. slow) accurately based on 
their contractile properties.
Regarding their interpretation, the 
authors in Deforges et al. (2009) concluded 
from their soma size measurements that 
swimming rescued large MNs and saved 
them from degeneration. However, in 
their MN classification the authors did 
not consider gamma-MNs, which have 
the smallest soma size in the ventral horn 
of the spinal cord. With that in mind, the 
results of the Deforges et al. (2009) could 
be reinterpreted in light of published liter-
ature on the soma size of various MN types 
in adult WT mice. Accordingly, MNs that 
were saved by swimming exercise (whose 
soma size is between 300 and 700 μm2) 
actually correspond to small alpha-MNs 
(whose soma size ranges between 450 and 
580 μm2; McHanwell and Biscoe, 1981; 
Ishihara et al., 2001), which innervate 
slow muscle fibers. Also, MNs that were 
reduced in proportion by swimming exer-
cise (whose soma size is <300 μm2) actually 
correspond to gamma-MNs (whose soma 
size ranges between 200 and 250 μm2; 
McHanwell and Biscoe, 1981; Ishihara 
et al., 2001), which are spared in the disease 
(Sobue et al., 1981). Moreover, the propor-
tion of large alpha-MNs (whose soma size 
is >700 μm2), which innervate fast muscle 
fibers, did not change with swimming, 
indicating that “true” large MNs were not 
protected. In sum, swimming exercise 
actually increased the proportion of small 
alpha-MNs, which innervate slow muscle 
fibers, even if large MNs were preferentially 
activated as claimed by the authors. This 
effect could be due to MN conversion from 
the large to small type by the effect of the 
training exercise. This reinterpretation is 
also consistent with a previous study in 
which swimming training in normal (i.e., 
non-transgenic) mice was shown to induce 
a fast-to-slow fiber conversion (Clément 
et al., 2008). In light of this reinterpreta-
tion, the Deforges et al. (2009) comes in 
agreement with Gordon et al. (2010) in 
which increased neuromuscular activ-
ity in G93A transgenic mice saved fast 
motor units by converting them to slow 
www.frontiersin.org April 2011 | Volume 2 | Article 18 | 3
ElBasiouny and Schuster Effect of training in ALS
Received: 22 March 2011; accepted: 12 April 2011; published 
online: 25 April 2011.
Citation: ElBasiouny SM and Schuster JE (2011) The effect 
of training on motoneuron survival in amyotrophic lateral 
sclerosis: which motoneuron type is saved? Front. Physio. 
2:18. doi: 10.3389/fphys.2011.00018
This article was submitted to Frontiers in Exercise 
Physiology, a specialty of Frontiers in Physiology.
Copyright © 2011 ElBasiouny and Schuster. This is an open-
access article subject to a non-exclusive license between the 
authors and Frontiers Media SA, which permits use, dis-
tribution and reproduction in other forums, provided the 
original authors and source are credited and other Frontiers 
conditions are complied with.
Sobue, G., Matsuoka, Y., Mukai, E., Takayanagi, T., Sobue, 
I., and Hashizume, Y. (1981). Spinal and  cranial 
motor nerve roots in amyotrophic lateral sclerosis 
and X-linked recessive bulbospinal muscular atro-
phy: morphometric and teased-fiber study. Acta 
Neuropathol. 55, 227–235.
Somani, S. M., and Husain, K. (1997). Interaction of exer-
cise training and chronic ethanol ingestion on anti-
oxidant system of rat brain regions. J. Appl. Toxicol. 
17, 329–336.
Sun, W., Funakoshi, H., and Nakamura, T. (2002). 
Overexpression of HGF retards disease progression 
and prolongs life span in a transgenic mouse model 
of ALS. J. Neurosci. 22, 6537–6548.
Miyazaki, H., Oh-Ishi, S., Ookawara, T., Kizaki, T., 
Toshinai, K., Ha, S., Haga, S., Ji, L. L., and Ohno, H. 
(2001). Strenuous endurance training in humans 
reduces oxidative stress following exhausting exercise. 
Eur. J. Appl. Physiol. 84, 1–6.
Nagao, M., Misawa, H., Kato, S., and Hirai, S. (1998). Loss 
of cholinergic synapses on the spinal motor neurons 
of amyotrophic lateral sclerosis. J. Neuropathol. Exp. 
Neurol. 57, 329–333.
Pinto, A. C., Alves, M., Nogueira, A., Evangelista, T., 
Carvalho, J., Coelho, A., de Carvalho, M., and Sales-
Luis, M. L. (1999). Can amyotrophic lateral sclerosis 
patients with respiratory insufficiency exercise? J. 
Neurol. Sci. 169, 69–75.


Sherif M Elbasiouny

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The effect of training on motoneuron survival in amyotrophic lateral sclerosis: which motoneuron type is saved?

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The Effect of Training on Motoneuron Survival in Amyotrophic Lateral Sclerosis: Which Motoneuron Type is Saved?

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