Amyotrophic Lateral Sclerosis (ALS) is an adult-onset progressive motor neuron disease that leads to paralysis, dysphagia, dysarthria, and ultimately, respiratory failure and death.[1,2] Evidence regarding the effects of exercise on ALS is limited, and the available research is controversial.[3] Prior to exercise prescription for a patient with ALS, age, cardiopulmonary status, medication use, prior level of physical activity, and trajectory of disease progression need to be taken into consideration.[4] The type of exercise chosen for a patient with ALS should be individualized based on the patient’s needs and condition.[4] This page will explore general exercise recommendations, response to exercise in ALS, and the effects of exercise at the cellular level in order to help identify appropriate exercise recommendations for individuals with ALS.

General Exercise Recommendations

Exercise and Human Studies

While some researchers have investigated the benefits of exercise on humans with ALS, the research is limited and frequently the interventions are poorly described. This may be due to several reasons, including epidemiological evidence that there is a higher rate of ALS in individuals performing intense physical activity and evidence that weakened muscle fibers may degenerate after resistance training in individuals with chronically denervated muscles.[5,6] These studies have primarily addressed moderate intensity physical activity, however the way in which moderate intensity is defined in the studies is often nebulous.[5,6] The results of these studies are summarized in Table 1.

Table 1. Summary of the outcomes of exercise interventions for individuals with ALS.

Study Intervention Results
Del Ballo-Haas et al[5] Moderate resistance training (parameters undefined) Individuals in exercise group had significantly less decline in ALSFRS, SF-36, MVIC scores; no difference in Fatigue Severity Scale (FSS).
Drory et al[6] Moderate intensity resistance training 15 minutes twice daily Decrease in Ashworth scale rating, less decline in MMT, ALSFRS. No change in SF-36, Visual Analogue Scale (VAS) for pain, FSS.
Sanjak et al[7] Body weight supported treadmill training 3 times per week for 60 minutes Improvement in ALSFRS, FSS 6MWT. No change in LE MVIC or 25 Foot Walk Test (25FWT).
Cheah et al[8] Inspiratory muscle training Improvement in Forced Vital Capacity (FVC), Vital Capacity (VC), inspiratory muscle strength. Less decline in 6MWT, Total Lung Capacity (TLC). No change in SF-36, ALSFRS-R, grip strength

Resistance Exercise

Two studies have addressed resistance training interventions in humans with ALS, all with positive results.[5,6] These studies have all investigated different parameters and have their individual strengths and weaknesses. As such, they will each be addressed individually. One randomized controlled trial investigated a six month moderate intensity resistance training program compared to a stretching program.[5] They found that individuals in the resistance training group had significantly less decline in ALSFRS score, SF-36 score and MVIC as measured at the legs and arms.[5] Unfortunately, the authors did not define moderate intensity or provide any parameters for frequency or duration, simply stating that programs were developed based on individual’s capabilities.[5] Although they did use intention to treat, they did suffer a high drop out rate and the study had low power.[5]

Another randomized controlled trial investigated a moderate intensity resistance training program performed 15 minutes twice daily.[6] This was compared to a control performing ADLs only. MMT, Ashworth score, ALSFRS score, Fatigue severity scale (FSS), VAS for pain and SF-36 were taken at 3, 6, 9 and 12 months, with results only published for 3 and 6 months due to large patient drop out by 9 and 12 months.[6] They found the exercise group had an improvement in spasticity over time, less decline in MMT scores and ALSFRS scores and no significant change in VAS for pain, SF-36 or FSS scores.[6] Intention to treat was not used in the statistical analysis, however and initial sample size was small (n=14 treatment, n=11 control) requiring caution to be used when interpreting the results.[6]

Endurance Exercise

One study was identified utilizing bodyweight supported treadmill training (BWSTT) on patients with ALS. Participants ambulated 3x/wk for 8 weeks using 40% body weight support.[7] They alternated between 5 minutes of work and 5 minutes of rest 6 times for a total length of an hour. Exercise intensity was self determined, with intensity not exceeding 13 on the modified Borg scale.[7] They found patients had an increase in ALSFRS score at 4 weeks that was maintained at 8 weeks, while 6MWT on the treadmill and over ground increased significantly.[7] No significant change was noted in FSS, 25FWT speed and upper and lower extremity MVIC.[7] This was a pilot study and included only nine participants with three dropping out, requiring caution when generalizing the results.

Figure 1. Body weight support treadmill training (BWSTT).

Inspiratory Exercise

One study utilized inspiratory muscle training on patients with ALS. This randomized controlled trial had participants complete a 12 week progressive inspiratory muscle training program.[8] There was an increase in FVC, VC, inspiratory muscle strength and less decline in TLC and 6MWT in comparison to the control group.[8] No significant difference was noted in SF-36 score, ALSFRS-R decline and grip strength.[8] While benefits were noted, caution must be used in interpreting these results due to the small sample size (experimental n=9).[8]


While more research needs to be done resistance training, aerobic training and inspiratory muscle training all appear to be beneficial for patients with ALS. Further research needs to be done to evaluate the ideal frequency, time and intensity and what combination of these exercises is most effective for the treatment and management of symptoms. Resistance training intensity should be no more than moderate and aerobic conditioning intensity should not exceed 13 on the modified Borg scale.

Response to Exercise in Animal Models of ALS

Moderate Intensity Exercise

The dosage and intensity of exercise needed to demonstrate valuable benefits in patients with ALS is unknown, yet numerous studies have utilized moderate intensity exercise to illustrate advantageous effects on ALS survival.[9,10,11] Additionally, the mechanisms behind what causes these changes and improved survival in mice requires further evidence. A major limitation in comparing these studies evaluating the effects of moderate intensity exercise is the absence of parameters of what moderate intensity exercise entails.

90 transgenic, male mice carrying the G93A human SOD1 mutation were used to analyze the effects of moderate intensity exercise (MEX), high intensity exercise (HEX) and no exercise (SED) on motor performance, body weight and motor neuron count in the ventral horn of the cervical, thoracic and lumbar spinal cord.[9] 30 wild type mice (WT) negative for the G93A mutation were used as controls in the study.[9] Motor neuron count and motor performance were analyzed at 70, 95 and 120 days of age.[9] The exercise protocol for the MEX and HEX mice consisted of an introductory 2-week training period in which all mice in these 2 groups performed the same amount and intensity of exercise starting at 30 days of age. The 2 weeks of training consisted of 20 minutes of running, at 5 and 10 meters/minute, 3 times per week.[9] Following the initial training period, the HEX mice ran for 60 minutes at 20 meters/minute, 5 days per week and the MEX group ran for 30 minutes at 10 meters/minute, 3 days per week.[9] The SED mice had no exposure to exercise other then walking in their cage. The mice were monitored for changes in body weight, motor performance and motor neuron count 2 times per week throughout the study.[9]

In regards to body weight, the MEX and HEX mice had significantly decreased body weight within 2 weeks of implementing the running regimen compared to the SED mice and this difference in weight continued throughout the remainder of the study.[9] Motor performance, measured using a rotarod apparatus, was performed for 60 seconds at 12 rpm until the mice fell off and the best of 3 trials was recorded.[9] Overall, the MEX mice were the only group to demonstrate a significant improvement in motor functioning and were able to maintain rotarod performance 30% longer (55.5+/-2.7 seconds) when compared to the sedentary mice (42.4+/-5.3 seconds).[9] Additionally, MEX mice demonstrated an overall delay in motor performance by 1 week when compared to the typical decline seen around 90 days of age in this transgenic population.[9,12] This improvement in motor performance seen via the rotarod is supported by the analysis seen in motor neuron count in the MEX mice. The MEX mice demonstrated a two-fold increase in motor neuron density at 95 days in the lumbar spinal cord compared to the SED mice.[9] The most shocking finding occurred in the lumbar spine of the MEX mice at 95 days, which demonstrated a significant greater motor neuron count compared to WT mice (3.62+/-0.27 x 106 cells/mm3 vs 2.29+/-0.16 x 106 cells/mm3).[9] At 120 days there were no significant differences between motor neuron counts in either the MEX or HEX groups compared to the WT groups in any area of the cord, whereas the SED mice had a significantly lower count compared to WT mice.[9] This study demonstrates increased survival for MEX mice as evidence by their delay in symptoms at 95 days, yet all mice were euthanized at 120 days of age so true longevity comparisons cannot be determined and this would be an essential area for further research.[9] Although there is great controversy between intensity and duration of exercise in this population, this study helps to illustrate the effects of moderate level intensity exercise on motor performance and motor neuron count in G93A transgenic male mice. However, due to routine euthanasia at 120 days true lifespan findings cannot be interpreted appropriately and further research in this area is warranted.[9]

Transgenic G93A SOD1 mice involved in 30 minutes of running 5 days/week at 13 meters/minute, which was considered a regular exercise program, compared to controls not performing any exercise demonstrated increased lifespan of 10 days for males and 5 days for females.[11] Mice in this study began their running program at 7 weeks and at 17 weeks of life the intensity of running speed was decreased until mice could not maintain a speed of 7 meters/minute.[11] Kaspar et al[10] has also demonstrated the positive effects of moderate intensity exercise on SOD1 mice survival, comparing not only exercise, but the role of IGF-1 in survival. Again, the results of studies demonstrating the effects of various intensities and forms of exercise are controversial and must be interpreted with caution especially when attempting to make parallels in humans with ALS since much of the work performed has been solely on animals.


The controversy behind the changes that occur during exercise in mice with ALS pose a difficult situation in regards to what type of exercise to recommend to patients with this disease. However, evidence demonstrates that moderate intensity exercise, which is variably defined in studies, is beneficial demonstrating a delay in motor function decline, increased survival and delayed symptoms in transgenic SOD1 G93A mice.[9,10,11] Although the mechanisms underlying these physiological and cellular changes are unknown, factors possibly influencing these positive changes include improvements in motor neuron counts and the role of IGF-1 in regard to exercise.[9,10]


Considering the findings in the previously described articles, the incorporation of exercise in patients with ALS at a moderate intensity may produce beneficial outcomes in regard to a variety of physical and cellular mechanisms. There is no pertinent data demonstrating any negative effects of moderate intensity exercise in this population. However, considering the variability in what is defined as moderate intensity in the literature and the fact that these previous studies were performed on transgenic mice, clinicians must be cautious generalizing this information to a population of humans with ALS.

High Intensity Exercise

Adaptations at the cellular level in the brain and skeletal muscles have been shown to occur with endurance exercise, which may result in benefits to individuals with ALS.[13] The benefits provided by this regular exercise may be due to defending against the deficit in energy associated with mitochondrial dysfunction.[13] In order to determine the functional outcomes associated with a regular, high-intensity endurance exercise training program in relation to ALS, Mahoney et al[13] developed a transgenic mouse model of ALS (SOD1-G93A).

Both transgenic G93A mice and wild-type littermate controls were assigned randomly to a high-intensity endurance training (END) group (n=14) or a sedentary (SED) control group (n=25).[13] Therefore, each group contained both transgenic and wild-type control mice. In the END group, the first 3 weeks of the program included a frequency of 3 days/week for 20, 25, and 30 min/day in the first through third week, respectively.[13] The remaining weeks of the program were completed for 45 min/day, 5 days/week.[13] A gradual increase from 9 m/min to 22 m/min was used throughout the training period in addition to a 10 minute warm up and cool down at 9-14 m/min at each session.[13]

Onset of symptoms, defined by bilateral hindlimb weakness with gait changes, in both the male and female transgenic mice was not influenced by the endurance training.[13] However, in male transgenic mice, there was a trend for an accelerated symptom onset, which was not seen for the female transgenic mice.[13] In male transgenic mice, but not female, endurance training resulted in a earlier death.[13] Motor performance, assessed using a rotarod, demonstrated significant decrease in the G93A mice as compared with wild-type mice.[13] Male G93A mice in the END and SED group demonstrated a significant decrease in motor performance at 112 and 119 days, respectively.[13] Female G93A mice in the END and SED group demonstrated a significant decrease in motor performance at 126 and 129 days, respectively.[13] Therefore, the high-intensity endurance exercise appeared to affect males to a greater extent than females.

Overall, high-intensity endurance exercise training does not appear to affect onset of clinical symptoms in G93A transgenic mice but it appears to accelerate death in male mice, but this effect was not demonstrated for females.[13] A similar trend was seen for motor performance, in which endurance training appeared to only accelerate the impairment in male mice.[13]

Carreras et al[9] compared the outcomes of motor performance and survival of motor neurons following either a moderate or high-intensity training program in transgenic SOD1 (G93A) mice. Results were also compared to SOD1 (G93A) transgenic line assigned to a sedentary group.[9] The study design including the exercise parameters and results regarding the effect of the moderate-intensity exercise regime can be found in the moderate-intensity section of this page.

Mice assigned to the training groups ceased the treadmill program at the onset of symptoms, which was earlier in the HEX group as compared with the MEX group.[9] Motor performance testing for each group was completed bi-weekly using a rotarod test.[9] Generally, motor performance throughout the lifespan showed that the HEX group had a decreased performance as compared to both the MEX and SED groups.[9] At a young age (70 days), motor neuron counts in the lumbar spinal cord demonstrated a significantly lower amount in both the HEX and SED groups as compared with age-matched wild-type controls.[9] The oldest group (120 days) of transgenic mice in the SED group demonstrated a significantly lower amount of motor neurons (approximately 50% less) in the ventral horn of the lumbar spinal cord as compared with age-matched wild-type controls.[9] In comparison, at 120 days, mice in both the exercise groups did not demonstrate any significant differences as compared to the age-matched wild-type mice in terms of motor neuron density.[9] Although not an outcome measure specifically analyzed in this study, the percentage of pre-mature death in the oldest group (age of 120 days) was greatest in the HEX group followed by the SED and MEX group, respectively.[9]

High-intensity exercise appeared to accelerate the onset of deficits in motor performance and demonstrated the greatest percentage of premature death as compared to the MEX and SED groups in a transgenic mouse model of ALS.[9]

Extensive exercise in ALS has become a focus because of the increased calcium loads and oxidative stress imparted on the body during sustained physical activity.[14] However, the continuous recruitment of motor neurons may help slow the disease progression.[14] To determine the effects of vigorous exercise a transgenic mouse model induced with overexpression of the human mutant form of SOD1 was used. In the study by Liebetanz et al[14], thirty-seven G93A mice were randomly divided into three groups. A vigorous group was subjected to 400 minutes of running on a motorized running wheel a day at a speed of 3.4 m/min starting at 5 weeks of age.[14] The mice in the sedentary group were corralled to the running wheel in the same way as the vigorous group; however, the wheel was set to a slow pace of .1 m/min.[14] The sedentary and vigorous group participated in the same amount of time on the running wheel a day. The control group of mice was undisturbed and housed in separate cages.[14] The disease onset was measured by grip testing, stride length and tight rope testing which was performed every three days.[14]

This study found no statistical difference in disease progress between the three groups according to the outcome measures or survival times.[14] The authors indicate that these results show that vigorous physical activity does not affect the pathogenesis or disease progression in transgenic mice induced with SOD1 mutations.[14].

In comparison to the above high intensity articles by Mahoney et al[13] and Carreras et al[9], this study is classified as vigorous exercise secondary to the time spent in physical activity and less by the actual intensity of the physical activity.


The determination of exercise intensity is important to in order to make appropriate recommendations for patients with ALS. It is important to determine the beneficial and detrimental effects of varying degrees of exercise intensity. The definition of high-intensity exercise is ambiguous, but the studies by Mahoney et al[13] and Carreras et al[9] used similar parameters for classifying high-intensity exercise. Overall, a trend appears for accelerated symptom onset in male transgenic mice with this higher level of exercise intensity.[9,13] Motor performance, assessed using a rotarod, demonstrated a greater propensity for impaired performance with high-intensity exercise as compared to a moderate-intensity exercise or a sedentary program.[9,13]

One potential mechanism for the negative effects seen following the high-intensity exercise program may be that this program overwhelmed the antioxidant system which may have lead to a an increase in oxidative stress in the motor neurons or muscles.[13] Another potential mechanism may be that the high-intensity exercise required a large amount of ATP that overwhelmed the capacity of the mitochondria.[13]

Extensive exercise, defined by duration of exercise and not by intensity, has been proposed to increase glutamate excitatory input and calcium influx, creating an excitotoxic state that may enhance motor neuron degeneration in ALS.[14] However, Liebetanz et al[14] found no statistical difference in a vigorously trained group of transgenic mice in terms of survival and disease progression which indicates that extensive exercise may not have the negative excitotoxic effects as previously thought.


Based on the findings from Carreras et al[9] and Mahoney et al[13], a high-intensity based exercise program would not be recommended for individuals with ALS. Although the study by Liebetanz et al[14] demonstrated no negative effects of disease progression and survival with an extensive exercise program, it was not performed at the level of intensity as Mahoney et al[13] and Carreras et al.[9] This evidence does not support the beneficial effects of high-intensity exercise in a mouse model of ALS.

Type of Exercise

To further study the effects of exercise on disease progression of ALS, two different types of physical activity were compared in a study by Deforges et al.[15] In this study, 105 transgenic G93A male mice with human SOD1 mutation were randomly divided into four groups at 70 days of age. The four groups were running based training on a speed regulated treadmill (maximum 13 m/min), swimming based training in an adjustable flow swimming pool (maximum 51 m/min), a sedentary group of mice, and a control group of mice that were placed in a pool without flow. [15] The intervention groups performed their activity 5 days a week for 30 minutes a day for 115 days of age or until death.[15] Disease onset was measured by myotony in the hind limbs of the mice and death was recorded when the mice could not stand up for 30 seconds after being placed on its side.[15] Other behavior characteristics were also monitored on a weekly basis such as grip strength, weight, spontaneous activity, holding a metal weight above their head, and an ambulatory test.[15] Histological testing of the lumbar spinal cord and immunohistochemical analysis were also performed after death to identify motor neuron death and apoptosis respectively.[15] Muscle mass testing of plantaris and soleus was also performed after death.

The results from this study indicated that disease progression and lifespan were dependent upon exercise type.[15] The mice in the swimming program had a significant delay in motor symptoms and a significant increase in mean survival when compared to the sedentary mice.[15] The mice in the swimming group also demonstrated a significant increase in the number of astrocyte and oligodendrocytes in their spinal cord in comparison to the other mice populations.[15] Caspase-3 measurements in the spinal cord of the mice groups showed decreased apoptosis in the swimming group as compared to all other mice populations.[15] As for muscle mass, the swimming group was able to reverse the hypoplasia of all the hind muscles measured and decrease the transition to slower twitch muscle fiber.[15]

It is also worth mentioning that the authors of this study describe the swimming program as high movement amplitude and frequency exercise and the running as a low amplitude and frequency exercise[15] according to a previous study by Grondard et al.[16] This study, performed in healthy mice, a 6 or 12 week swimming intervention in the adjustable flow swimming pool was compared to a 6 or 12 week running program for 60 minutes, 5 days a week.[16] The mice in the swimming intervention group (6 and 12 week) had increased frequency and amplitude of hind limb movements when performing the swimming interventions.[16] Further supporting the evidence for the swimming intervention as a high intensity exercise was the fact that motor neuron analysis during the swimming intervention preferentially recruited larger diameter muscle fibers as running recruited more small diameter muscle fibers, analogous to fast twitch and slow twitch muscles.[16] From these results, it can be implied that the mice participating in the swimming intervention in the study by Deforges et al.[15] were participating in high intensity exercise.


In a mouse exercise model, it appears that swimming as compared to running recruits fast-twitch muscle fibers, and when performed in an adjustable flow swimming pool, is deemed high-intensity exercise secondary to the frequency and amplitude of hind limb movements required of the animal to keep its head above water. With this being said, the high-intensity swimming intervention in the mouse model from Deforges et al[15] produced increased survival time, decreased apoptosis, increased immune cell activation, and decreased muscle morphology changes[15]. This study is indicative of the positive benefits of not only a swimming intervention in the mice model of ALS but also of high-intensity exercise. A drawback of this study is the inability to relate it to the human ALS population. It would be difficult to make swimming a high intensity exercise in humans because of the inability to control limb frequency and amplitude. Further human studies in this area are needed to determine if swimming alone could reap positive benefits in the human population of ALS.

Effect of Exercise on Cellular Components of ALS

Oxidative Stress

As stated in the cell biology portion of this page, it has been theorized that oxidative stress is a contributing factor in the pathogenesis of ALS. Researchers have noted an increase in the generation of reactive oxygen species (ROS) in patients with ALS, as well as a number of abnormal mitochondrial changes.[17] The literature has also noted that exercise has been shown to increase the production of reactive oxygen species in humans and animals.[18] This has frequently thought to be related to an increase in free radicals from the electron transport chain in the mitochondria and oxidation of xanthine oxidase.[18]

Exercise, Mitochondria and Oxidative Stress

Since the electron transport chain, which takes place in the mitochondria, has been linked to an increase in ROS and mitochondrial dysfunction has been implicated in ALS it is important to note the impact exercise has on mitochondria. Research has demonstrated changes in the mitochondria as a result of exercise.[19] These adaptations seem to largely be the result of mitochondrial fission and fusion, which are regulated primarily by mitofusin 1 and mitofusin 2 (Mfn 1 and Mfn 2) proteins.[19,20] These proteins control fusion through interaction with optic atrophy protein 1.[19,20] In fission they interact with dynamin-related protein 1 (Drp1) and human fission protein 1 (hFis1).[19,20] There have been changes noted in mitochondria through both acute and chronic exercise. Acutely, intense exercise has been shown to impair oxidative phophorylation with a concurrent increase in ROS generation and an increase in mitochondrial fission and decrease in mitochondrial fusion. This was thought to be related to an inhibition of Mfn2 and Drp-1 and an increase in Fis1.[19] Repeated bouts of exercise have been shown to lead to an expansion of the mitochondrial retinaculum and an increase in mitochondrial respiratory capacity, which in turn could cause increases in ROS through an increase in oxidative phosphorylation.[19] Many of these changes seemed to be related to elevated levels of Mfn1, Mfn2 and Fis1 during the 24hr recovery period post exercise, relating to increased levels of mitochondrial adaptations.[19] Low to moderate levels of oxidative stress were shown to alter substrate selection to enhance glycolysis and decrease oxidative phosphorylation, while prolonged or high levels of oxidative stress may cause apoptosis.[19] It is important to keep this information in mind when determining exercise intensity in ALS patients. Since ALS patients have been shown to have chronically increased levels of oxidative stress and increased rates of apoptosis in affected areas of motor neuron degeneration minimizing the amount of additional oxidative stress is important.[17,21] Since intense and long duration exercises have been indicated in increased cell death, these types of exercise should be avoided. Low to moderate intensity exercise was not shown to increase apoptosis through ROS and mitochondrial dysfunction. It can be assumed that these forms of exercise may not be harmful to patients with ALS. It also is important to give this population an adequate recovery period so beneficial mitochondrial adaptations can occur.

Human Studies on ROS and Exercise

Studies on regular exercise have been shown to slow the aging process and decrease the likelihood of contracting oxidate stress related diseases. In a controlled trial of graded exercise, Sicilliano et al found that ALS patients had a significantly higher lactate mean base and peroxidation markers at 40% max power on a cycle ergometer, max power and after 30 minutes rest as compared to a control group.[17] The increased levels of peroxidation markers, specifically lipoperoxides, demonstrates the increased acute oxidative stress patients with ALS are under.[17] Normally, SOD1 and other antioxidant proteins reduce peroxides and decrease oxidative stress.[17] With ALS, this pathway does not function correctly resulting in increased levels of oxidative stress. In a healthy population exercise has been shown to increase levels of SOD1, SOD2 and glutathione peroxidase 1 (GPx1), all of which are known antioxidants.[22] This further indicates that intense or long duration physical activity should be avoided due to the potential of causing an acceleration in apoptosis and thus the progression of the disease. However, it would indicate regular exercise, since SOD2 and GPx1, antioxidant proteins not indicated as dysfunctional in ALS, are upregulated. This could potentially help ameliorate the effects of the defective SOD1 protein on oxidative stress and ROS.

Apoptosis and Exercise

The role of cellular apoptosis in ALS is just one of the many possible mechanisms underlying the overall disease process, but the rate and specific action at which this happens is not clearly defined. Although there is no specific research performed in this area on either transgenic mouse models or humans with ALS, research in the area of apoptosis and the effects of moderate intensity exercise has been analyzed in healthy human skeletal muscles directly following an exercise bout and also in aged rats following 12 weeks of exercise training.[23,24]

In a study focusing on the effects of moderate intensity exercise for a prolonged period of time, which was defined as 60% of VO2 peak for 2 hours, in healthy humans determined that a single bout of exercise at this intensity does not produce significant changes in apoptosis within skeletal muscle.[23] During the 2 hour exercise bout muscle biopsies of the vastus lateralis were obtained at 60 minutes and 120 minutes one in each leg and blood samples were obtained initially every 15 minutes for the first 2 readings and then every 30 minutes until the bout of exercise was complete at 120 minutes.[23] Specifically, a moderate intensity bout of exercise over a 2-hour period resulted in significant changes at the metabolic level and minimal changes in regard to apoptosis. Anti-apoptotic measures analyzed in this study included XIAP, Hsp70, Bcl-2 and ARC while the pro-apoptotic measures analyzed included AIF, Smac and BAX.[23] In regard to apoptosis there were no significant changes in either the pro- or anti-apoptotic factors following a single session of moderate intensity endurance exercise.[23] Metabolic changes were detected as evidence by significant decreases in glycogen, lactate and PCr at 60 minutes and 120 minutes in these exercised humans.[23] Moderate, prolonged exercise bouts in humans did not alter pro- or anti-apoptotic proteins or processes, but rather demonstrated greater changes in metabolic components of the body.[23]

Although patients with ALS most often pass away at a young age, the mechanisms leading to muscle disuse, atrophy and degeneration are in some ways comparative to what occurs with increasing age in healthy humans. The rate of apoptosis has been seen to increase with increased age and more specifically related to Bcl-2 family of proteins and ultimately activation of caspase-3 in this cellular mechanism.[24,25] As seen on the ALS cellular biology page, Bax and Bcl-2 play important roles in the intrinsic apoptotic pathway shown to impact the pathogenesis of ALS. A study comparing the effects of exercising rats and sedentary rats either aged or young demonstrated decreased expression of pro-apoptotic proteins in the skeletal muscle of aged, exercising rats.[24] The rats in the exercise group performed exercise at approximately 75% VO2 max, which consisted of running at 15 meters/minute for 1 hour, 5 times per week for 12 weeks.[24] The intensity of exercise in this study was not clearly defined as either moderate or high intensity. Not only were changes seen in regard to Bax and Bcl-2 proteins, but overall identifiers for apoptosis including DNA fragmentation and cleavage of caspase 3 were altered.[24] Specifically, there was evidence demonstrating decreased levels of Bax, increased levels of Bcl-2 ultimately leading to increased Bax/Bcl-2 ratio in aged, exercising rats.[24] Additionally, there were decreases in DNA fragmentation and cleaved caspase 3 protein compared to sedentary aged rats.[24] Exercise essentially plays an imperative role in the apoptotic pathway in aged rats leading to beneficial outcomes not only in identifiers of apoptosis, but also positive alteration in levels of Bax and Bcl-2 proteins.[24]


It is difficult to pinpoint the benefits and disadvantages to performing exercise in patients with ALS in regard to cellular apoptosis considering there are no articles specifically identifying these outcomes in this patient population and the studies described above are either on aged, exercised rats or healthy, active humans. However, considering the results obtained in the studies above a couple assumptions can be made. First, a single bout of moderate intensity exercise does not result in changes in either pro- or anti-apoptotic protein expression in skeletal muscle, but rather strictly entire body and metabolic alterations.[23] Caution must be taken when interpreting these results considering these were healthy, active humans and overall physiological and cellular analyses were performed immediately following exercise and further changes were not measured at a longer period following exercise. Secondly, 12 weeks of exercise in aged rats demonstrated increased Bcl-2, decreased Bax and an increase in Bax/Bcl-2 ratio ultimately illustrating a reversal of apoptotic factors found to occur in aging.[24] Again, clinicians must be aware that these changes were not only seen in rats, but essentially aged rats and technically this cannot be generalized to patients with ALS.


There are many limitations in regard to these studies. Overall, there is a gap in the literature on this topic related to either transgenic mouse models of ALS or humans with ALS. Future research should be conducted on the effects of exercise and cellular apoptosis mechanisms in patients with ALS or transgenic mouse models of ALS.


Considering the results found in the above studies, one can interpret and assume that exercise could prove beneficial in the ALS population since positive apoptotic changes in skeletal muscle were seen in aged rats and there were no negative changes associated with skeletal muscle apoptosis following one bout of moderate exercise in humans.[23,24] However, the intensity and duration of exercise needed to result in positive outcomes in regard to cellular apoptosis in skeletal muscle of patients with ALS is not known.


As stated on the ALS cell biology page, PGC-1α is a transcription co-activator that works together with other proteins to influence adaptive thermogenesis, mitochondrial biogenesis, metabolism of glucose/fatty acid, switching of fiber types in the skeletal muscle, and development of the heart.[26] The process of mitochondrial biogenesis involves a coordinated expression of both the nuclear and mitochondrial genomes that are responsible for encoding the mitochondrial proteins.[27] PGC-1α complexes with the mitochondrial transcription factor (Tfam) only in instances where Tfam is linked to the displacement loop (D-loop) region of the mitochondrial DNA (mtDNA).[28] The D-loop region of the mtDNA is the initiation site of transcription.[28] PGC-1α also acts as a co-activator for nuclear respiratory factor (NRF-1), which is a transcription factor involved in mitochondrial biogenesis.[29] The effect of exercise on PGC-1α has not been explored specifically in individuals with ALS. However, transgenic mouse models of ALS have demonstrated the beneficial functional and cellular level effects of an over-expression of PGC-1α, which can be seen on the ALS Cell Biology page.[30,31] Studies of the effects of exercise on PGC-1α have not been completed in transgenic models of ALS, however the influence of exercise has been demonstrated in wild-type and mtDNA mutated transgenic lines. The mitochondrial abnormalities associated with ALS can be seen on the ALS Cell Biology page, which demonstrates the importance of looking at PGC-1α since it is involved in mitochondrial biogenesis. The use of a mtDNA mutator transgenic line may, therefore, be related to ALS. The following table presents information from various studies on the effect of exercise, of varying intensity and duration, on PGC-1α.

Murine Model Studies of PGC-1α

Table 2. Summary of results for the effect of exercise on PGC-1α.

Author Subjects Exercise Intervention Effect on PGC-1α Conclusion
Safdar et al[28] 36 wild-type male and female C57B1/6J mice at 3 months of age were randomly assigned to one of three groups. Group 1: Endurance Exercise (END) (n=12): Treadmill running at 15 m/min for 90 min Group 2: Endurance Exercise with 3 hours of rest (END+3h) (n=12): Treadmill running at 15 m/min for 90 min plus 3 hours of rest Group 3: Sedentary (SED) control (n=12): No exercise intervention PGC-1α skeletal muscle content was not increased for the END group immediately after exercise. However, the END+3h group demonstrated a significant increase in PGC-1α skeletal muscle content as compared to the other two groups. A significant increase in nuclear PGC-1α content and mitochondrial PGC-1α content was seen in the END group as compared with the SED control group. A trend for even further improvement in PGC-1α content was seen in the END+3h group. Following the END exercise, an immediate significantly increased mRNA expression of mitochondrial transcripts in the skeletal muscle including PGC-1α, Tfam, δ-aminolevulinate synthase (ALAS), citrate synthase, and cytochrome c were seen as compared to the SED group, which demonstrated maintenance or further increase following 3 hours of rest. END exercise led to an increased incidence of Tfam binding to the mtDNA D-loop in addition to a significantly increased amount of complexing of PGC-1α with Tfam at this location as compared with sedentary controls. As compared with SED controls, END exercise led to an immediate significant increase in binding of NRF-1 to its initiation site and the increase was exacerbated in the END+3h group. Exercise appears to cause a movement of PGC-1α from the cytosol to the mitochondria and nuclei in order to influence mitochondrial biogenesis.[28] END exercise appears to provide an adequate stimulus for increasing PGC-1α content, mRNA expression of mitochondrial transcripts, and movement of this protein to the nucleus and mitochondria in order to influence mitochondrial biogenesis.[28]
Terada et al[32] Wild-type male Sprague-Dawley rats between the ages of 5-6 weeks assigned to one of two experimental groups and compared with sedentary age-match caged controls. Group 1: High-intensity intermittent swimming exercise (HIE): 14 bouts of 20 sec swimming, carrying weight approximately equaling 14% body weight Group 2: Low-intensity prolonged swimming exercise (LIE): 2, 3-hour sessions of swimming with a 45-minute period of rest between sessions Group 3: Sedentary age-matched caged controls As compared to controls, epitrochlearis muscle PGC-1α content significantly increased at assessment periods 2, 6, and 18 hours after HIE but not immediately following exercise. By the 6-hour post exercise assessment, PGC-1α content was significantly increased in additional muscles including the triceps, plantaris, and the gastrocnemius. Significant increases in the epitrochlearis PGC-1α content were seen immediately following LIE as well as at the 6 and 18 hour post-exercise assessments as compared with controls. No significant difference between the two groups in terms of PGC-1α content at the 6 hour post-exercise assessment were noted.[32] An increase in skeletal muscle PGC-1α content is shown to occur regardless of the intensity of the exercise (high versus low).[32]
Wright et al[27] Wild-type male Wistar rats assigned to one of two exercise groups. Group 1: 2, 3-hour sessions of swimming with 45 minute rest break between sessions Group 2: 2-hour session of swimming The acute bout of the swimming exercises led to significantly increased epitrochlearis muscle expression of proteins regulated by PGC-1α (succinate-ubiquinone oxidoreductase and estrogen-related receptor) as compared with sedentary controls without an immediate increase in PGC-1α protein expression. ALAS expression was also increased immediately following the exercise but this was not a significant increase as compared to sedentary controls. The acute bout of exercise significantly increased the DNA binding of NRF-1 as compared to sedentary controls prior to the increase in the expression of PGC-1α. An immediate response to an acute bout of the exercise was the significant increase in the mRNA of mitochondrial proteins (ALAS, cytochrome c, and citrate synthase) as compared with sedentary controls, which was prior to the increase in PGC-1α. 3 hours following the swimming exercise, a significant increase in epitrochlearis muscle PGC-1α was demonstrated with a trend for further increase over the subsequent 15 hours post-exercise as compared to sedentary controls. Additionally, following the 2 hour bout of swimming exercise, a significant increase in the amount of nuclear PGC-1α content was seen in the epitrochlearis muscle as compared with sedentary controls.[27] Acute endurance exercise leads to an immediate increase in the expression of proteins regulated by PGC-1α, an increase in the mRNA levels of mitochondrial proteins, and an increased DNA binding of NRF-1 with a delayed increase in the expression of PGC-1α. The initial phase of mitochondrial biogenesis may be mediated by activation of already existing PGC-1α proteins which increases the expression of mitochondrial proteins it regulates with a later increase in PGC-1α associated with maintaining or enhancing the biogenesis.[27]
Safdar et al[33] mtDNA mutator mice (PolG: PolgAD257A/D257A) and wild-type littermates (PolgA+/+). PolG mice were randomly assigned to an END or SED experimental group at 3 months of age. Group 1: PolG mtDNA mutator-END (n=18): Treadmill training 3x/week, 45 min/day, 15 m/min for 5 months. Warm up and cool down for 5 minutes at 8 m/min each Group 2: PolG mtDNA mutator-SED (n=18): No exercise intervention Group 3: Wild-type control littermates (n=18) Significantly lower levels of nuclear PGC-1α and Tfam were seen in the PolG-SED group as compared to wild-type littermates. The PolG-END group demonstrated increased levels of nuclear PGC-1α content and a significantly increased content of Tfam in the skeletal muscle as compared to wild-type littermates, which demonstrates a movement towards mitochondrial biogenesis. Irregularities that were present in the mitochondria of the PolG mutator mice were abolished in the endurance exercise group, demonstrating the beneficial effects of endurance exercise on improving mitochondrial morphology.[33] Long-term END exercise appears to promote mitochondrial biogenesis in mice with mutations of the mtDNA and mitochondrial dysfunction. In response to END exercise, PGC-1α appears to promote mitochondrial biogenesis.[33]


The use of acute and chronic endurance exercise appears to provide a mechanism to increase the expression of PGC-1α to influence mitochondrial biogensis.[27,28,32,33] Research indicates that the initial phase of mitochondrial biogenesis may be mediated by activation of previously existing PGC-1α proteins with a later increase in PGC-1α associated with maintaining or enhancing the biogenesis.[27] This is supported by a general trend for increased PGC-1α content in the hours of rest following an acute bout of endurance exercise.[27,28,32] Additionally, endurance exercise yielded increases in the binding of transcription factors co-activated by PGC-1α (Tfam and NRF-1), which may contribute to mitochondrial biogenesis, prior to an increase in PGC-1α.[27,28] Since current evidence indicates that elevated levels of PGC-1α are seen following high and low-intensity exercise[32], if high-intensity exercise is not appropriate or feasible for a patient, beneficial effects of this protein may still be achieved. Even though PGC-1α increased with acute bouts of exercise[27,28,32] it also appears that long-term exercise is beneficial in promoting the positive effects of mitochondrial biogenesis in mice with mitochondrial mutations.[33] In a transgenic mouse model of ALS, positive benefits on disease progression were demonstrated with the use of a regular exercise program over a 10-week period.[11] The effects of endurance exercise on PGC-1α in humans have shown similar results to that of the murine model studies. Pilegaard et al[34] demonstrated the effect of lower extremity knee extensor endurance exercise on the skeletal muscle of healthy humans that led to an approximate 7- to 10-fold increase in the mRNA content of PGC-1α, which demonstrated its peak gain at 2-hours post-exercise. Russell et al[35] demonstrated the effects of a chronic (3 times per week for 6 weeks) endurance exercise running program at an intensity of approximately 60-80% VO2max in healthy males yielded an approximate 3-fold increase in skeletal muscle mRNA content of PGC-1α in addition to an increased skeletal muscle protein content of PGC-1α.


These articles offer valuable information on the role of exercise on PGC-1α, however, in order to more accurately understand the effects for individuals with ALS, it would be recommended to looks at the effects of exercise on this protein in a transgenic model of ALS and then in individuals with ALS. This gap in the literature demonstrates the need for future work in this area.


The use of endurance exercise, regardless of the intensity, appears to be beneficial in helping to promote mitochondrial biogenesis by increased expression of PGC-1α and additional proteins regulated by PGC-1α in addition to an increased binding of transcription factors associated with this process.[27,28,32,33] The beneficial functional and cellular level effects of over-expression of PGC-1α demonstrated in transgenic mouse models of ALS,[30,31] suggest that exercise may beneficial to this patient population. Therefore, the use of endurance exercise, at an individually determined intensity, may be an appropriate recommendation for individuals with ALS but further research using transgenic mouse models of ALS and individuals with ALS will be needed to make more accurate exercise recommendations.

Heat Shock Proteins

Heat shock proteins (HSPs) are activated in response to oxidative stress, and may be implicated in neurodegenerative diseases such as ALS and Multiple Sclerosis (MS).[36] For a description of the function of HSPs and their role in MS,click here. The Hsp70 family is made up of some of the most commonly found HSPs in the body, and increased expression of Hsp70 has been shown to decrease cellular apoptosis and increase Bcl-2 expression, contributing to the neuroprotective effects of HSPs.[36,37,38]

A study by Naito et al[39] looked at the change in skeletal muscle HSP72 following a 10-week endurance exercise program in non-mutated young and old rats. A total of 24 wild-type Fisher 344 rats were randomly assigned to one of four groups; young sedentary control group (n=6), old sedentary control group (n=6), young endurance training group (n=6), and old endurance training group (n=6).[39] Young rats were 3 months of age (n=12) and old rats were 23 months of age (n=12).[39] Prior to randomization into groups, all rats were acclimated to the treadmill with a daily, weeklong treadmill walking program with no incline for 5-10 min/day at 10-15 m/min.[39] The treadmill endurance program was completed 5 days/week for the 10-week period.[39] The daily duration of exercise for both endurance training groups was 10 and 35 minutes for the first and second weeks of the program, respectively.[39] For the remainder of the program, a daily duration of 60 minutes/day was used for both age groups.[39] A treadmill grade of 15% was utilized throughout the entire 10-week program for both age groups.[39] The speed of the treadmill was different between the young and old age groups, however the aim was to establish an equal relative intensity between the groups (approximately 77% VO2peak).[39] The treadmill speed for the first two weeks of endurance training program for the young group of rats was 24 m/min, which increased by 1 m/min for the subsequent 8 weeks of the program.[39] The first two weeks of the endurance program for the old group of rats included a treadmill speed of 14 m/min that increased by 1 m/min for the remaining weeks of the program.[39]

The effects of sedentary behaviors and endurance exercise on the skeletal muscle HSP72 was evaluated following the 10-week period.[39] No significant difference was found between the two sedentary control groups in regards to levels of HSP72 content in the soleus, plantaris, and gastrocnemius muscles.[39] All previously stated muscles demonstrated a significant increase in HSP72 expression for both endurance training groups as compared with age-matched controls.[39] The amount of increase of HSP72 was significantly less for the old versus the young endurance training group for muscles with predominantly fast-twitch muscle fibers.[39] Overall, for old and young rats exposed to a prolonged endurance exercise program, increased HSP72 levels were demonstrated in the skeletal muscles as compared to age-matched sedentary controls.[39]

Oxidative stress as well as the elevation of body temperature that occur with exercise both play a role in the alteration of HSP expression during exercise.[36] Studies have shown an increase in Hsp72 following both acute exercise and periods of long-term exercise training, leading to improved response to stressors.[39,40] Due to the neuroprotective characteristics of heat shock proteins and their response to stress, it can be theorized that the increase in heat shock protein response to stress that occurs following exercise may be protective in individuals with ALS. Studies investigating a potential pharmacologic therapy for ALS, arimoclomol, have demonstrated that this drug acts as an amplifier of the normal heat shock protein response to stress, and arimoclomol administration led to improvements in lifespan and muscle function in G93A transgenic mice.[41,42] This further supports that increased expression of HSPs with exercise may be beneficial for individuals with ALS.

The onset of disease in ALS occurs in adulthood[1] with a typical age of onset occurring in the fourth and fifth decades of life[43], demonstrating the importance of the use of older animal models to help determine the benefits of exercise in the later stages of life. It would be recommended that this type of study be completed in mouse models of ALS in order to help better understand the specific implications to this disease process. Further research is needed to determine the optimal duration and intensity of exercise training to optimize the heat shock protein response to stress.



Innate immunity, specifically neutrophils, is a primary first responder when a pathogen enters the body.[44] However, the mitochondria and reactive oxygen species (ROS) play a major role in maintaining an adequate balance of neutrophil spontaneous apoptosis.[44] In pathological diseases, the neutrophil population can be poorly regulated through ROS leading to an increase in neutrophil apoptosis which causes bacterial/fungal infections or a decrease in neutrophil apoptosis which leads to accumulation of cells.[44]. In ALS, the innate immune system is actively up-regulating cells in order to preserve motor cells. An increase or decrease of neutrophil apoptosis in ALS could lead to an increased risk of an upper respiratory infection, an already troublesome condition for this population.[44]

In a study by Syu et al[44], researchers looked at the rate of neutrophil apoptosis in healthy sedentary, male subjects in two randomly assigned exercise groups: acute severe exercise (ASE) and chronic moderate exercise (CME). ASE has been found to impede immunity reactions in human subjects by increasing oxidative stress and release of inflammatory cytokines.[44] CME is associated with improved immune modulation and a decreased risk for infections.[44] In the study, the ASE/CME group performed a bout of severe exercise on a cycle ergometer with continuous increments in workload until heart rate reached at least 90% of age predicted maximum prior to initiation of the study.[44] For the following 2 months, the CME group performed 30 minutes of exercise, 5 days a week, at 60% maximal workload as compared to the initial testing followed by 2 months of detraining and severe exercise testing every month.[44] The ASE group performed the severe exercise testing as previously described once every 2 months.[44] Blood samples were taken in both groups prior to initiation of the severe exercise testing and after the severe exercise testing.[44] Neutrophils from the blood samples were isolated and cultured.[44] Parts of the blood samples were frozen for later analysis of glutathione (an antioxidant), oxidative stress (defined as the ratio glutathione disulfide and glutathione), basal cytosolic ROS, and Annexin-V binding to the neutrophils (a marker of apoptosis).[44]

In this study, the initial bout of severe exercise testing, regardless of group allocation, showed an increase oxidative stress and ROS, as measured by an increase in glutathione disulfide to glutathione and increased basal cytosolic ROS, respectfully.[44] Of significant importance, the CME intervention with detraining did not show an increase in the ROS status and demonstrated a slowed spontaneous neutrophil apoptosis, as observed by lower annexin-V binding, after one month of exercise.[44] The negative effects of the ASE training completely disappeared in the CME intervention group after one month of initiation of CME.[44] The positive effects of CME were even maintained throughout the detraining period.[44]


Although this study does not include patients with ALS, it does bare significant importance on the decision to engage patients with ALS in exercise. As shown, ASE can have a negative impact on neutrophil apoptosis, leaving one’s immune system vulnerable to infection.[44] On the other hand, CME could possibly stabilize neutrophil apoptosis and slow production of ROS that could progress the disease. Of particular importance in this study is that these decreased levels of neutrophil apoptosis and decreased ROS were maintained over an extended 2 month period of detraining.[44] This finding could be beneficial to maintaining neutrophil activation after a patient with ALS has progressed to the end stage of the disease.

Insulin-Like Growth Factor-1 (IGF-1)

Research has demonstrated that exercise results in increased levels of serum IGF-1.[10] So, considering this discovery one would hypothesize that exercise in patients with ALS may increase serum IGF-1 leading to prolonged survival. Kaspar et al[10] took a three-fold approach to this concept by analyzing the effects of exercise on SOD1 mutated mice by looking at exercise dosage related to increased motor performance, exercise in SOD1 mice and levels of serum IGF-1 and the results of early exercise in SOD1 mice with overexpression of IGF-1.[10] The initial study compared SOD1 mice exposed to 0, 2, 6 or 12-hour access to a running wheel at 40 days of life, which is considered early to the onset of symptoms at about 90 days.[10,12] The group exposed to 6 hours had the greatest longevity of 163 days compared to 147 days in the 12-hour group, 129.5 days in the 2-hour group and 122.5 in the non-running (NR) group.[10] The 6 hour and 12 hour groups demonstrated a significant difference in rotarod performance at 130 days compared to the 0 and 2 hour groups, illustrating a dose effect that the mice required at least 6 hours of running exposure to demonstrates gains in motor function.[10] Secondly, the levels of circulating and spinal cord IGF-1 were analyzed in three different groups of SOD1 mice: early running (ER), AAV-IGF-1 injection at 90 days to intercostal and hindlimb muscles and non-running group (NR) to help determine the impact IGF-1 has on survival in these mice.[10] The group injected with AAV-IGF-1 had the greatest extension of survival by 29 days compared to controls and the ER group had increased survival by 21 days.[10] Serum IGF-1 was slightly increased in mice exposed to ER compared to the AAV-IGF-1 group, yet when evaluating the lumbar spinal cords of these mice the IGF-1 levels were much lower in the ER and NR groups compared to the AAV-IGF-1 groups in the spinal cord.[10]

Lastly, the comparison of early running (ER), late running (LR), no running (NR), AVV-IGF-1 and AAV-IGF-1 plus ER were studied to determine the effects of combined action of exercise plus over expression of IGF-1 in these SOD1 mutated mice.[10] The main finding demonstrated a collaborative effect of early running plus overexpression of IGF-1, which resulted in a median 83-day increase in survival among this group compared to the NR controls.[10] Even the mice exposed to running at 90 days (LR), demonstrated favorable effects in increased median survival of 15 days with solely exercise and a 37 day increase in survival with exercise plus an overexpression of AAV-IGF-1 compared to NR controls.[10] In regard to motor performance measured via the rotarod, ER plus IGF-1 had an 80-day extension in survival rate compared to the NR controls.[10] In relation to motor neuron health, the ER group, AAV-IGF-1 and combined AAV-IGF-1 plus ER groups had significant delayed motor neuron death compared to the NR controls, but no significant differences were found with wild-type mice.[10] The results of this delay in motor neuron death and damage may be due to the variation in apoptotic proteins found in these subgroups of mice. The NR mice demonstrated slightly elevated levels of Bax, the pro-apoptotic protein, while the ER mice demonstrated large increases of 2.16-fold and 4.65-fold of the anti-apoptotic proteins Bcl-xL and Bcl-2, which were proven to be independent of AAV-IGF-1 delivery and solely a result of exercise.[10]

Implications and Recommendation

This evidence helps establish the idea that exercise provides a neuroprotective effect in this population independent of AAV-IGF-1 delivery, yet the role that exercise plays in controlling the expression of IGF-1 in these SOD1 mice has yet to be explained.[10] However, one can conclude that a moderate level of exercise can produce relatively positive effects on SOD1 mutated mice in regard to neuroprotection as illustrated via increased anti-apoptotic proteins and when supplemented with AVV-IGF-1 the effects of exercise are promoted even greater.

Figure 2. AAV-IGF-1

SMN Protein

One proposed benefit of exercise in the similar neurodegenerative disease, spinal muscular atrophy, is the increased splitting of the SMN2 gene that leads to more SMN protein.[45] Similarly spinal muscular atrophy and ALS have been suggested to have a decrease in the SMN protein secondary to inappropriate replications of the SMN genes.[45] In the study by Grondard et al,[46] mice that were SMN-null were injected with one copy of human SMN2 gene and were trained regularly on a running wheel for 100 meter a day versus an untrained control group. Not only did the trained mice have a statistically significant longer life but also demonstrated increased amounts of anterior horn cells in the lumbar spine.[46] Furthermore, muscle phenotype of the calf musculature was maintained throughout the running protocol in the trained group of mice.[46]

The results of this study in mice with spinal muscular atrophy depicts muscle conservation in the calf musculature, prolonged life, and increased motor neurons in the anterior horn of the lumbar spinal cord because of the shift to appropriate splicing of the SMN2 gene that exercise induced.[46] These results could be beneficial to patients with ALS secondary to the decreased amounts of SMN protein found in the spinal cord of mice models. It could be inferred that patients with ALS and low SMN protein could benefit from a regular exercise program, specifically running, for motor neuron preservation of the calf musculature and possibly prolonged life. However, a limitation to this study is the lack of evidence in the ALS population.


It has been demonstrated that the expression of metallothioneins (MTs), including MT-1, MT-2, and MT-3, is decreased in the spinal cords of patients with ALS.[47] Metallothioneins are responsible for regulating cellular zinc levels as well as reducing oxidative stress, and MT deletion has been shown to contribute to the progression of ALS.[48,49]

Exercise has been shown to increase oxidative stress by increasing free radicals in the body, and MTs are released to help rid the body of excess free radicals and protect cells from their harmful effects.[49] One study demonstrated that MT-1 and MT-2 expression is increased in skeletal muscle following exercise in healthy men following a 3-hour exercise bout of cycling, which may play a role in protecting against oxidative stress following exercise.[49]

Another study by Hashimoto et al[50] implemented a 1- and 2-week treadmill running exercise program in normal male mice for 30 minutes daily with sedentary controls. The mRNA levels of MT-1, MT-2, and MT-3 were significantly increased at 12 hours following a single bout of exercise, and MT-1 and MT-2 continued to demonstrate upregulation at 12 hours following the final exercise session of the 2-week program.[50] The expression of MT-1/2 was increased in the spinal cord following the 2-week exercise program compared to control mice, and, while MT-3 also increased, the increase noted in MT-1/2 was higher and occurred at a faster rate than the increase in expression levels of MT-3.[50]

The cellular mechanisms by which exercise impacts the progression of ALS remain unclear, though studies have demonstrated the involvement of metallothioneins in the pathology of ALS.[48] The study by Hashimoto et al[50] demonstrates that exercise leads to an increase in metallothioneins in the spinal cord in mice. The role of metallothioneins in the prevention of neuronal death in ALS suggests that exercise may be beneficial in increasing the presence of this neuroprotective protein in the spinal cord.[48,50] Further research is needed in mice models of ALS to determine whether these findings are similar in mice demonstrating an ALS phenotype.

Sexual Differences

To further explore the effects of exercise of transgenic mice induced with human SOD1 mutations, Veldink et al,[51] demonstrated that exercise extended the life and delayed onset of the disease for female hSOD1 mice in comparison to male hSOD1 mice regardless of number of human copies of SOD1. Both high copy hSOD1 and low-copy hSOD1 transgenic lines of mice were utilized in the study.[51] The study also included wild-type littermates as a control group for comparison.[51] A total of 65 low-copy hSOD1 (n=35 males, n=30 females) were assigned randomly to either an exercise or sedentary group.[51] 16 wild-type littermates (n=8 males, n=8 females) were assigned randomly to an exercise or control group.[51] The exercise program began when the mice were 8 weeks of age and mice completed a running program on a motorized treadmill for 45 min/day, 5 days/week at a speed of 16 m/min.[51] It was estimated that the mice were working at approximately 80% of VO2max at this treadmill speed.[51] However, high-copy hSOD1 mice were unable to tolerate this treadmill speed and therefore completed the exercise training at 12 m/min.[51] The authors also created a second part of the study which included the same exercise protocol with only female high-copy hSOD1 mice (n=20) that were assigned randomly to an exercise or control group.[51] For this part of the study, 13 sedentary males were used as controls.[51]

Sedentary female mice with both low-copy hSOD1 and high-copy hSOD1 demonstrated a significant delay in disease onset, as measured by the hindpaw extension reflex, as compared to hSOD1 sedentary males (25 and 21 days, respectively).[51] In the low-copy hSOD1 female group, exercising mice demonstrated a delay in the onset of disease of 48 days as compared with the female hSOD1 sedentary group, a result that was significant.[51] For the high-copy hSOD1 female mice, a 13 day delay in the onset of disease was seen with exercise as compared with female hSOD1 sedentary mice but this was not a significant finding.[51] Exercise did not appear to influence the disease onset for males with the low-copy hSOD1 as compared with sedentary male hSOD1 mice.[51] For hSOD1 mice that were sedentary, sex did not appear to play a role in altering survival time.[51] Survival times were not significantly different when comparing low-copy hSOD1 mice that completed the exercise program or that were sedentary.[51] The only significant finding related to alteration of survival was in the exercising female high-copy hSOD1 mice, in which a 4 day delay was seen as compared to female hSOD1 mice that were sedentary.[51] No difference was noticed in motor neuron histology testing of the lumbar ventral horn between any group (exercise/sedentary) regardless of sex.[51]

Overall, sex did appear to influence the onset of disease for female hSOD1 mice, in which there was later onset as compared with male mice.[51] The use of exercise appears to lead to a delayed disease onset in females as compared to males.[51] Additionally, a lengthened survival was seen for the exercising female high-copy hSOD1.[51]


For female patients with ALS, the onset of disease typically occurs at an older age, which may demonstrate the neuroprotective effect of estrogen.[51] However, more research is needed in this area in order to fully determine the extent of this hormonal influence.

Conclusion and Exercise Recommendations

There is limited evidence regarding the effects of exercise on the pathophysiology of ALS, and the evidence that is available is controversial.[3] Due to the characteristics of this disease, exercise studies are difficult to perform in this population. ALS is a rapidly progressing disease, making the completion of long-term endurance studies a challenge due to high drop out rates. While some studies have shown beneficial effects from exercise, some research has shown negative effects of exercise in individuals with ALS.[5,6,7,8] The controversial state of current evidence regarding the effects of exercise on the symptoms, lifespan, and function of individuals with ALS, as well as the inherent risks of exercise (overwork damage, fatigue, etc) may pose a challenge for recruiting research participants. Despite these challenges, research in mouse models of ALS, though still limited, has provided another method for exploring the effects of exercise on the pathophysiology of ALS.

Both endurance training (at an intensity of 60-80% VO2max) and acute bouts of exercise appear to lead to increased levels of PGC-1α, though studies regarding the effects of exercise on PGC-1α have not yet been performed in mouse models of ALS.[28,34,35] It has been demonstrated that a single bout of moderate intensity exercise (60% of VO2max for 2 hours) does not impact apoptosis at the cellular level, demonstrating no negative effects of exercise on this primary pathological feature of ALS.[23] An increase in heat shock protein response has been noted following endurance training, indicating a possible benefit of exercise for individuals with ALS, as heat shock proteins perform antioxidant functions, aiding in cellular protection from oxidative stress.[39,40] Exercise also increases the amount of IGF-1 and metallothioneins, both which may have positive effects on the disease process of ALS.[10,49,50,52]

High intensity exercise has not yet been shown to be beneficial, and some studies have shown detrimental effects of high intensity exercise in ALS.[9,13] Therefore, high intensity exercise is contraindicated in this population until further evidence is available demonstrating its beneficial effects.

Based on the currently available evidence regarding the effects of exercise on the cellular components of ALS, both moderate intensity resistance exercise and endurance training are appropriate exercise prescriptions for this population at this time.[9,10,11,52] Moderate exercise was poorly defined in the available literature, but it is generally accepted that exercise intensity and mode of exercise should be determined on an individual basis, taking into consideration a variety of factors including age, disease progression, cardiopulmonary status, medication use, and prior levels of physical activity.[4] Exercise should be progressed gradually with adequate periods of rest in between sessions, while continuously monitoring the patient’s response. More research is necessary to determine the optimal frequency, intensity, and duration of training in individuals with ALS.

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