Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. It causes progressive and cumulative physical disabilities in patients, and leads to eventual death due to respiratory muscle failure. The disease is diverse in its presentation, course, and progression. We do not yet fully understand the cause or causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. Currently, we rely on a multidisciplinary approach to symptomatically manage and care for patients who have ALS. In this article, the authors review the literature on the role of exercise in patients who have ALS, and briefly compare what is known about exercise in other neuromuscular diseases.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system, involving the cortex, brainstem, and spinal cord. It causes progressive and cumulative physical disabilities in patients, and leads to eventual death due to respiratory muscle failure. The incidence of ALS is 1 to 2 cases per 100,000 population per year, and the prevalence is 4 to 7 cases per 100,000 population because of the short mean survival time . It is estimated that 10,000 to 25,000 people are affected by ALS in the United States at any time. The disease is diverse in its presentation, course, and progression. We do not yet fully understand the cause or causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating it. Currently, we rely on a multidisciplinary approach to manage and care for patients who have ALS symptomatically . Rehabilitation plays an essential role in the care of patients who have ALS, along with pharmacologic interventions, respiratory support, nutritional supplements, communication devices, and social and psychologic support . In the authors’ experience, one of the most frequently asked questions by patients who have ALS is whether exercise is beneficial.
In this article, the authors review the literature on the role of exercise in patients who have ALS, and briefly compare what is known about exercise in other neuromuscular diseases. Specifically, they ask
- 1.
What types of exercise (stretching, resistance/strengthening, and aerobic/endurance training) have been examined in patients who have ALS?
- 2.
What kinds of exercise regimens (intensity, duration, and frequency) are beneficial for patients who have ALS?
- 3.
What are the demonstrated benefits and how are they measured?
The authors also reviewed animal studies for comparison. They hope to determine whether clinicians may safely recommend a structured exercise regimen as a treatment intervention for patients who have ALS.
Importance of exercise for the general public
Exercise is widely promoted to the general population because of its great benefit to health and wellbeing. In 1996, the American Surgeon General published a health report recommending (1) regular physical activity, consisting of moderate-intensity exercise for at least 30 minutes on most days of the week, for the general population of all ages; (2) more vigorous intensity of physical activity and of longer duration for greater health benefit; and (3) strength-developing exercises at least twice a week for most adults, to supplement the benefits of cardiorespiratory endurance exercise.
The health benefits of physical activity include enhancement of the cardiovascular, respiratory, musculoskeletal, and endocrine function, and psychologic wellbeing . Moreover, exercise lowers the risks of developing chronic diseases that are associated with inflammation, such as coronary heart disease , hypertension , colon cancer , and diabetes mellitus . The authors briefly discuss the potential mechanisms by which exercise improves health and reduces inflammation, based on data that are mostly derived from healthy people and animal studies.
Mechanisms by which exercise benefits health
Myofiber remodeling
During exercise, myofibers are activated, either by mechanochemical or mechanoelectric signals, which lead to an increased intracellular calcium concentration and subsequent signaling cascades. An intricate network of coordinated gene expressions, which are not yet fully understood, is then responsible for myofiber remodeling. Type I slow-twitch oxidative myofibers are induced after exercise training, as evidenced by the induction of myoglobin, troponin I slow, and myosin heavy chain type I molecules . The transition of myofibers from type II to type I may allow for enhanced muscle adaptability and a greater insulin-induced glucose uptake, thus presenting a lower risk for developing diabetes mellitus .
With exercise also comes an enhanced beta-oxidation of fatty acids, which is caused by the induction of the peroxisome proliferator activated receptor and its coactivator 1 (PGC-1α) . This results in an enhanced metabolism of fat and a reduction of adipose tissues, and, conceivably, contributing to the consequent reduction of inflammation associated with sedentary lifestyle. Resistance training also causes muscle hypertrophy, which is mediated by insulin-like growth factor (IGF-1) and the target of rapamycin (TOR) signaling pathway .
Antioxidative and anti-inflammatory adaptation
Besides modifying the muscle fiber types and mass, exercise also causes an initial increase in free radical production and oxidative stress, which is counteracted by the subsequent activation of the endogenous antioxidative defense mechanism . A new homeostasis is achieved; thus, regular exercise of moderate intensity appears to result in a lower basal state of oxidative stress level . Depending on the duration and intensity of the exercise and the age of the person, the myokine interleukin-6 is produced following exercise. It contributes to health by activating downstream anti-inflammatory pathways and enhancing the metabolic and immunologic response , which ultimately benefits the cardiovascular system in healthy and disease states .
Central nervous system stimulation and plasticity
Exercise has an effect on the central nervous system; reorganization and an increase in motor neuron excitability have been demonstrated in the motor cortex and the spinal cord following resistance training . The central nervous system thus has a role in contributing to increased strength following exercise training.
Neuroendocrine effect
Exercise also activates the hypothalamic-pituitary-adrenal (HPA) axis, increases the production of cortisol and catecholamines, and enhances cellular metabolism . However, the interplay of exercise on the neuroendocrine system, including the HPA axis, the thyroid function, and the reproductive hormones, is complex. The response of the neuroendocrine system depends on the intensity, type, and duration of exercise, as well as the age, gender, and fitness level of the person. Although exercise in general benefits health, in some cases such as chronic intense training, it may affect the neuroendocrine system negatively . This possibility should be borne in mind whenever exercise regimens are being recommended.
Mechanisms by which exercise benefits health
Myofiber remodeling
During exercise, myofibers are activated, either by mechanochemical or mechanoelectric signals, which lead to an increased intracellular calcium concentration and subsequent signaling cascades. An intricate network of coordinated gene expressions, which are not yet fully understood, is then responsible for myofiber remodeling. Type I slow-twitch oxidative myofibers are induced after exercise training, as evidenced by the induction of myoglobin, troponin I slow, and myosin heavy chain type I molecules . The transition of myofibers from type II to type I may allow for enhanced muscle adaptability and a greater insulin-induced glucose uptake, thus presenting a lower risk for developing diabetes mellitus .
With exercise also comes an enhanced beta-oxidation of fatty acids, which is caused by the induction of the peroxisome proliferator activated receptor and its coactivator 1 (PGC-1α) . This results in an enhanced metabolism of fat and a reduction of adipose tissues, and, conceivably, contributing to the consequent reduction of inflammation associated with sedentary lifestyle. Resistance training also causes muscle hypertrophy, which is mediated by insulin-like growth factor (IGF-1) and the target of rapamycin (TOR) signaling pathway .
Antioxidative and anti-inflammatory adaptation
Besides modifying the muscle fiber types and mass, exercise also causes an initial increase in free radical production and oxidative stress, which is counteracted by the subsequent activation of the endogenous antioxidative defense mechanism . A new homeostasis is achieved; thus, regular exercise of moderate intensity appears to result in a lower basal state of oxidative stress level . Depending on the duration and intensity of the exercise and the age of the person, the myokine interleukin-6 is produced following exercise. It contributes to health by activating downstream anti-inflammatory pathways and enhancing the metabolic and immunologic response , which ultimately benefits the cardiovascular system in healthy and disease states .
Central nervous system stimulation and plasticity
Exercise has an effect on the central nervous system; reorganization and an increase in motor neuron excitability have been demonstrated in the motor cortex and the spinal cord following resistance training . The central nervous system thus has a role in contributing to increased strength following exercise training.
Neuroendocrine effect
Exercise also activates the hypothalamic-pituitary-adrenal (HPA) axis, increases the production of cortisol and catecholamines, and enhances cellular metabolism . However, the interplay of exercise on the neuroendocrine system, including the HPA axis, the thyroid function, and the reproductive hormones, is complex. The response of the neuroendocrine system depends on the intensity, type, and duration of exercise, as well as the age, gender, and fitness level of the person. Although exercise in general benefits health, in some cases such as chronic intense training, it may affect the neuroendocrine system negatively . This possibility should be borne in mind whenever exercise regimens are being recommended.
Exercise and neuromuscular diseases
In a recent meta-analysis by the Cochrane review group of 35 exercise trials in muscle diseases from 1966 to 2002, only two studies met rigorously defined criteria for inclusion . To be included, studies have to be randomized, use a nonintervention group as a comparison, and have a standardized training protocol of at least 10 weeks’ duration. One study involved patients who had fascioescapulohumeral muscular dystrophy and the other, myotonic dystrophy. The investigators concluded that in patients who had either of these two diseases, moderate intensity strength training showed no significant benefit or harm.
A more inclusive review of exercise studies in patients who had neuromuscular diseases found 58 studies to be of sufficient methodological quality for analysis . The investigators examined the effects of strengthening exercise, aerobic exercise, or a combination of the two, in diseases of the anterior horn cells, nerves, and muscles. Nearly all the studies included an individualized, progressive strengthening protocol as defined by established guidelines for healthy adults and the protocols were of moderate intensity. Despite variations in the types of exercises and muscle used, the interventions in nearly all disease groups caused no adverse effects. The investigators concluded that the combination of strengthening and aerobic exercises is likely to be effective (level II evidence) in patients who have muscle diseases, and that aerobic exercises may be effective (level III evidence) for patients who have muscle diseases. In addition, breathing exercises may be effective (level III evidence) for patients who have myasthenia gravis and neuromuscular diseases. Evidence was insufficient of a beneficial effect of strengthening alone in all neuromuscular diseases included in the review.
Rehabilitation for patients who have stroke and multiple sclerosis deserves some mentioning here, because these patients often exhibit spasticity, which is also commonly seen in patients who have ALS. A systematic review of progressive resistance strength training in poststroke patients showed that such training can increase muscle strength without increasing spasticity or reducing range of movement . A review of the literature on physical training and multiple sclerosis also showed that exercise is beneficial for these patients, without adverse effects . These findings are encouraging and suggest that exercise may be safely applied to ALS patients who have spasticity.
Exercise and amyotrophic lateral sclerosis (human studies)
Below, the authors review studies of exercise, grouped by the types of exercise regimen, in patients who have ALS.
Stretching exercise
Stretching, or exercises that improve flexibility, can maintain muscle and soft tissue extensibility and joint mobility, and can prevent contractures . Muscle weakness in ALS can cause an imbalance between agonist and antagonist muscle groups, predisposing patients who have ALS to muscle shortening, joint contractures, and poor posture. Claw hand deformity is a good example of this disparity and occurs in ALS patients. Stretching weakened and unaffected muscle groups prevents contractures, maintains good postural alignment, reduces pain from hypomobility, and helps lessen the potential complexities of functional mobility and performing activities of daily living. Because stretching does not impact muscle strength, it is often used as a placebo or a control in studies examining the benefits of other types of exercise in ALS ( Table 1 ). It, itself, has not been randomized against nonstretching in the study of exercise in ALS.
| Types of exercise | Studies | Outcomes |
|---|---|---|
| Stretching | No RCT | |
| Enhances connective tissue | ||
| Strengthening | Bohannon et al, case study | Improved isometric strength in 14 U/E muscles |
| Myofiber remodeling | Decreased isometric strength in 4 muscles | |
| Reduces inflammation | Subjective improvement of functions | |
| Enhances metabolism | Drory et al, randomized | Improved function (ALSFRS) at 3 months |
| CNS adaptation | Improved spasticity (ASS) at 3 months | |
| No changes in MMT, fatigue, and QOL | ||
| Bello-Haas et al, randomized | Improved function (total and subtotal ALSFRS-R) at 6 months | |
| Improved QOL (SF36) at 6 months | ||
| Aerobic | Sanjak et al, case control | Examined biophysical and metabolic responses: |
| Myofiber remodeling | Increased oxygen cost of work | |
| Reduces inflammation | Decreased lipid metabolism | |
| Enhances metabolism | Pinto et al, case control | Improved the rate of functional decline (Spinal Norris) |
| CNS adaptation | Improved QOL on FIM scale, but not Bartels | |
| Siciliano et al, case control | Increased lactate and lipid peroxides | |
| Precocious anaerobic threshold achieved |
Related posts:
Glial Cells in ALS: The Missing Link?
Androgen Receptor Function in Motor Neuron Survival and Degeneration
Motor Unit Number Estimation in the Assessment of Performance and Function in Motor Neuron Disease
Designing Clinical Trials in Amyotrophic Lateral Sclerosis
Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis
Clinical Trials in Spinal Muscular Atrophy
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