Physical activity as an exogenous risk factor for amyotrophic lateral sclerosis: a review of the evidence

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. The only established epidemiological risk factors for ALS are male sex and increasing age. The role of physical activity has been debated as an environmental risk factor. Over the last decade multiple studies have attempted to delineate the architecture of ALS. These have not yet established definite risk factors, often due to low-powered studies, lack of focus on at-risk genotypes and sub-optimal methodology. We have conducted a review of all the studies published between 2009 and December 2021. The free text search terms were [(motor neuron disease) OR (MND) OR (Amyotrophic Lateral Sclerosis) OR (ALS)] AND [(Exercise) or (Physical Activity) or (PA) or (sport)]. We identified common themes, for example soccer, head injury and the physiological mechanisms that differ in ALS patients. We have analysed the relevant, available studies (n = 93), highlighting the underlying reasons for any reported discrepancies. Overall, we have found that the more highly powered studies using validated exposure methodologies, linked strenuous, anaerobic physical activity as a risk factor for ALS. Future large-scale studies focusing on specific at-risk genotypes and physical activity should be conducted to confirm this finding. This will strengthen the evidence already surrounding strenuous physical activity as an environmental risk factor for ALS and allow advice to be given to at-risk family members. Increasing our understanding of the genetic-environmental interactions in the pathophysiology of ALS will allow for the possibility of developing preventative therapeutic approaches.

Keywords: amyotrophic lateral sclerosis; environmental risk factor; motor neuron disease; strenuous physical activity.

Figure 1

PRISMA flow diagram. PRISMA flow diagram detailing the bibliographical searches carried out, including the number of papers screened and the reasons for any publications which were excluded from the analysis.

Figure 2

Physiological response to acute exercise in healthy humans and mice. (A) Transcriptome analysis of peripheral blood mononuclear cells (PMBCs) reveals that 22% of the biological pathways differentially expressed following acute exercise are significantly enriched with ALS-associated rare genetic variants. The top 30 pathways by P-value are shown. All pathways depicted pass multiple testing correction (FDR < 0.05). (B) The physiological impact of acute exercise in humans measured by gene expression changes in PBMCs. Acute exercise induces an inflammatory response [increasing natural killer (NK) cells, Th1 and Th2 activation, B cell receptors, T cell receptors]. It also increases oxidative stress, apoptosis and upregulates angiogenesis and wound healing pathways [platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF) and epidermal growth factor (EGF)] signalling and dysregulates metabolic pathways, decreasing leptin. (C) The important gene expression changes in the motor neurons from mice following prolonged regular daily exercise for 6 weeks. Mouse data are depicted as it is not possible to obtain details of the motor neuron transcriptome from living human subjects. The neurotrophic factors and receptors (Cntf, Lifr, Actvr2a) are increased. Genes involved in signalling (Pka1b, Narp, CamkIId) are also increased. Genes involved in ion channels (Kcnd3, Kcne2, Kcnk3) are increased and (Cacng8) is decreased. Genes involved in cytoskeleton reorganization (Arhgap, Gna12, Limk, Acta) are increased, these are involved in neurite outgrowth. P2Y9 and Pctaire, involved in neurite retraction, are decreased.

Figure 3

The pathophysiological mechanism of ALS. The complex pathophysiological mechanisms in ALS. The labels highlighted in bold show which pathological mechanisms in ALS are increased further by strenuous exercise. ER = endoplasmic reticulum.

Figure 4

Future recommendations. (A) A large sample of C9ORF72-ALS patients should be studied using a validated questionnaire, such as the HAPAQ, to establish in a larger scale study whether strenuous PA exacerbates the clinical phenotype. This may allow lifestyle advice to be provided to at-risk family members with this genetic subtype of ALS. (B) Skin biopsies can be taken from participants with ALS and healthy controls. The fibroblasts can be reprogrammed to generate motor neurons, astrocytes and microglial cells. These human cell models can be studied to assess in detail pathophysiological changes when subjected to stresses e.g. hypoxia and oxidative stress, which operate during strenuous PA. The differences in stress response can be analysing using RNA sequencing, investigating any dysregulation of the response transcriptome in cell models of ALS compared to controls. (C) There are known transcriptomic changes present in PBMCs following strenuous exercise. The genetic factors predisposing to dysregulation of the physiological pathways can be analysed in large datasets of whole genome sequencing from a large sample of ALS patients. (D) Animal models of genetic subtypes of ALS beyond SOD1 can be studied to evaluate the effect of strenuous PA on disease parameters such as age of onset and survival. For example, for C9ORF72 ALS relevant Drosophila, zebrafish and mouse models have been generated, which will allow evaluation of this genetic–environmental interaction. Figure created using BioRender.com.