Exercise training: thinking ahead to counteract systemic manifestations of spinal muscular atrophy.

Abstract

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by mutations in the Survival Motor Neuron 1 (SMN1) gene and remains a leading genetic cause of infantile death worldwide. Recent gene and molecular therapies showed striking benefits in SMA patients (Groen et al. 2018). So far, the US Food and Drug Administration (FDA) has approved the use of two therapies for SMA patients, the SMN1 gene replacement therapy AVXS-101 (Zolgensma, Novartis/AveXis), and the antisense oligonucleotide nusinersen (Spinraza, Biogen) that modulates pre-messenger RNA splicing of the Survival Motor Neuron 2 (SMN2) gene. These therapies, in conjunction with improvement of medical support, will certainly improve morbidity and survival in even the weakest SMA patients. Identifying additional approaches to improve the well-being of SMA patients remains a priority for researchers and clinicians. Motor neurons are selectively vulnerable to SMN deficiency, and their damage accounts for the earliest manifestation of SMA. However, SMN is ubiquitously expressed in human cells and critical to various cellular pathways. For instance, SMN regulates the assembly of the spliceosome machinery, which is critical for the functionality of all cell types. Thus, understanding the full impact of SMN deficiency both within and outside the central nervous system is critical. Given the pleiotropic benefits of exercise, it is reasonable to speculate that exercise training could be useful to improve functional outcomes in SMA patients. Exercise improves whole-body metabolic homeostasis, including rates of energy production, blood flow and substrate utilization. Exercise training induces adaptations in multiple tissues throughout the body and is considered a non-pharmacological co-therapy for neuromuscular diseases, including SMA (Lewelt et al. 2015; Ng et al. 2018). In a recent issue of The Journal of Physiology, Ng et al. (2019) tested the molecular mechanisms underlying exercise-induced effects in a SMA mouse model (i.e. Smn2B/−) (Ng et al. 2019). This study not only demonstrated that a single bout of exercise is able to activate classic exercise signalling molecules, such as AMP-activated protein kinase and p38 mitogen-activated protein kinase, but also that a single bout of acute exercise remarkably increased the full-length SMN mRNA expression levels in the skeletal muscle of Smn2B/− mice (Ng et al. 2019). A striking finding from the Ng et al. (2019) study is that exercise training increased the inclusion of SMN exon 7 in SMN mRNA by ∼40% (Ng et al. 2019). SMA is caused by mutations in the SMN1 gene that result in reduced functional SMN protein expression. However, the paralogue gene SMN2 produces ∼10% functional SMN protein because it undergoes alternative splicing including the removal of exon 7. In fact, the number of SMN2 copies inversely correlates with phenotypic severity since patients with more SMN2 copies have higher full-length SMN mRNA levels. Thus, targeting the inclusion of exon 7 in the SMN transcript is a useful strategy to further increase functional SMN protein content. The fact that an acute bout of exercise can increase SMN full-length mRNA levels strongly suggests that acute exercise regulates the spliceosomal processes keeping exon 7 in the right sequence when transcribing the SMN2 gene. The authors propose that this process could be regulated by the activation of peroxisome proliferator-activated receptor γ coactivator 1α, which was indeed increased in the nucleus of skeletal muscle from Smn2B/− mice and previously demonstrated by many independent groups to be a key player in acute and chronic exercise effects in the skeletal muscle. The Ng et al. (2019) study is not without limitations. First, mice performed exercise at 3 m/min until exhaustion, which was empirically determined. A protocol until exhaustion will most likely not be translated to clinical studies and findings cannot be directly compared to the effects of exercise in healthy mice since the intensity and duration of exercise are not the same for all mice. Second, even though the Smn2B/− model is less severe than other SMA models and mice were mature enough to perform some exercise, there is still a fast progression of symptoms, which limits proper investigation of the mechanisms underlying the chronic effects of the treadmill exercise protocol. Previous studies have demonstrated chronic effects of physical activity in increasing the maturation of the motor units and delaying motoneuron death (Biondi et al. 2008; Ng et al. 2018), but a deeper investigation of the molecular mechanisms behind these effects is still necessary. Third, the authors did not include a healthy exercised group in the study design, which can be considered a major limitation. It is not possible to determine if the effects of exercise on signalling pathways occur to the same degree as expected in healthy muscle conditions. Despite the limitations presented above, these findings have key clinical implications and stress the need for open discussion about the role of exercise training as a potential regulator of SMN levels in skeletal muscle. Indeed, identifying additional and/or complementary therapies for SMA is an important topic since many patients are not eligible for gene therapy with AVXS-101 due to a major risk of an immune response to the vector. Currently, AVXS-101 is indicated only for SMA patients less than 2 years old and it was not evaluated in patients with advanced SMA. In addition, the oligonucleotide nusinersen is delivered intrathecally, and thus in effect mainly to the central nervous system cells. Thus, identifying additional therapies to replace systemic levels of SMN is still necessary. The SMA drug pipeline includes at least six additional drugs being tested in clinical trials and many other potential therapeutic targets in preclinical exploratory stages. The use of exercise protocols as a strategy to increase SMN levels in peripheral tissues fosters enthusiasm that exercise might be not only a co-adjuvant therapy to improve well-being of patients with SMA, but also a direct strategy to counteract SMN deficiency and systemic manifestations of SMA. In conclusion, Ng et al. (2019) provide insights into the mechanisms involving exercise-induced benefits in SMA and a foundation for future studies to uncover the role of exercise training as a co-therapy for SMA patients under gene and/or molecular therapy. Identifying additional strategies to improve functional outcomes in SMA patients remains a high priority and exercise training certainly needs to be appreciated as a potential non-pharmacological approach to counteract systemic manifestations in SMA patients. The author does not have any conflicts of interest. Sole author. No funding was received to assist in the preparation of this article.