Amyotrophic lateral sclerosis and the neuroprotective potential of exercise

When confronted with the devastating diagnosis of amyotrophic lateral sclerosis (ALS, or motor neurone disease), patients are desperate for information particularly in regards to causation and treatment. Inevitably, discussion turns to lifestyle-related issues, and often the role of exercise. Unfortunately, this is a complex, largely unresolved area of disease management, with the potential benefits of exercise in ALS remaining an open discussion between physician and patient. In America, ALS is also known as Lou Gehrig's disease, named after the famous New York Yankees baseballer (Fig. 1). Gehrig was a superb athlete, and as with most ALS patients, there seemed to be no apparent reason for him to contract this universally fatal disease at the young age of 35, and die 2 years later. Other seemingly random cases have subsequently been described in high-performance athletes. However, a recent retrospective study of more that 7000 footballers from the Italian professional leagues established that standardized morbidity ratios were increased for the development of ALS, particularly younger onset (Chioet al. 2005). For unexplained reasons, footballers who played for more than 5 years, particularly in an active midfield position, were at highest risk. Other studies have suggested a raised risk of ALS in marathon runners, and further epidemiological investigations are currently underway in rugby populations. Figure 1 Lou Gehrig, the New York Yankees baseballer, who developed ALS in his mid-thirties. Although ALS is typically sporadic, approximately 10% of cases are familial, whereby two or more family members are clinically affected. The exact pathophysiological mechanisms underlying neurodegeneration in both familial and sporadic ALS have yet to be defined. Inheritance of familial ALS is usually autosomal dominant, often linked to mutation of the copper/zinc superoxide-dismutase-1 gene (SOD-1) resulting in the typical adult-onset ALS phenotype (for review, see Vucic & Kiernan, 2009). The key function of the SOD-1 enzyme involves free radical scavenging, with the enzyme catalysing the conversion of the superoxide anion to molecular oxygen and hydrogen peroxide. The processes underlying ALS appear multifactorial, involving complex interaction between genetic factors and molecular pathways, with resultant damage of critical target proteins and organelles within the motor neurone. In terms of any pathophysiological link between exercise and the development of ALS, oxidative stress, excessive free radical production and increased glutamate stimulation may all accompany normal motor neurone activation. However, it is plausible that such processes may potentially become neurotoxic as a result of exercise and excessive activition in susceptible individuals. Dysfunction of the energy-dependent, axonal Na+/K+ electrogenic pump may also be an integral factor contributing to motor neurone loss in ALS (Vucic et al. 2007). In addition to regulating the resting membrane potential, the Na+/K+ pump exerts a significant role in the restoration of Na+ and K+ gradients after high-frequency impulse activity. Specifically, after a period of prolonged activity, the accumulated intracellular Na+ ions increase Na+/K+ pump activity resulting in membrane hyperpolarization. In the setting of a dysfunctional Na+/K+ pump, exercise may conceivably result in accumulation of intracellular Na+ and thereby provoke disruption of resting membrane potential. Secondary effects mediated by changes in intracellular Na+, including reverse activation of the Na+–Ca2+ exchanger, would lead to intracellular increases in Ca2+ concentration, activation of calcium-dependent enzyme systems and neuronal death. Of relevance, widespread loss and dysfunction of Na+/K+ pump function have been demonstrated in the SOD-1 ALS mouse model. Such discussion remains largely hypothetical and relates more to a potential role for exercise in the causation of ALS. How then, should the treating neurologist advise patients once diagnosed with ALS regarding their lifestyle and specifically, the role of exercise? Unfortunately a recent Cochrane analysis cited a lack of randomised clinical trial data that may guide appropriate discussion concerning the potential benefits or risks of aerobic type exercise in ALS (Dalbello-Haas et al. 2008). Similarly, there is limited information concerning resistance training, although recent pilot studies involving inspiratory muscle training suggest potential benefit, with larger multicentre studies currently underway (Cheah et al. 2009). Given a lack of clinical trial information, the study by Deforges and colleagues in this issue of The Journal of Physiology is timely and potentially encouraging (Deforges et al. 2009). Specifically, using a targeted programme involving swimming, the authors demonstrated improved motor function, protection of motor neurones and their supportive cell structures, and ultimately increased lifespan in the G93A transgenic SOD-1 mouse model of ALS. These findings in a SOD-1 mouse model of ALS must be interpreted with caution, particularly given the fact that of the many (>100) trials undertaken in SOD-1 mouse models of ALS, none of the positive findings from animal studies have translated into meaningful therapy in human ALS. As it stands, the recent findings related to exercise clearly need further validation, but perhaps they may serve to increase the momentum for larger scale, exercise-based clinical trials in ALS patients.