Exercise Can Help Increase Functional SMN Protein and Supplement SMA Treatment, Researchers Say

Exercise can help increase levels of the survival motor neuron protein, and could potentially be used as an adjunctive therapy to treat spinal muscular atrophy (SMA), according to a recent study.

The study, “Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice,” was published in The Journal of Physiology, and was highlighted in the same journal in an opinion article, titled “Exercise Training: Thinking Ahead to Counteract Systemic Manifestations of Spinal Muscular Atrophy,” by Christiano R. R. Alves, PhD, of the Massachusetts General Hospital, Harvard Medical School.

SMA — a neurodegenerative disorder characterized by the gradual loss of motor neurons (the nerve cells responsible for controlling voluntary muscles) in the spinal cord, leading to muscle weakness — is normally caused by mutations in the SMN1 gene, which encodes for the survival motor neuron (SMN) protein that is essential for motor neuron survival.

However, the SMN2 gene can also produce the SMN protein, and it usually remains unaffected in SMA patients. SMN2 is known to influence the course of the disease, depending on the number of copies present.

To date, the U.S. Food and Drug Administration has approved the use of two therapies for SMA: Zolgensma (developed by AveXis, which is owned by Novartis) and Spinraza (developed by Biogen). These therapies have improved the survival of SMA patients but they may not be suitable for all patients.

Identifying additional and/or complementary therapies for SMA is important as many patients are not eligible for gene therapy with Zolgensma due to major risks of immune responses.

Furthermore, so far, Zolgensma is approved to treat only SMA patients who are younger than 2, and it has not been evaluated in patients with advanced SMA.

In addition, Spinraza is delivered intrathecally (into the spine), and thus is mainly effective in the cells of the central nervous system. Therefore, identifying additional therapies to increase systemic (throughout the whole body) levels of SMN is necessary.

“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,” Alves wrote.

Exercise is generally associated with significant benefits such as improvements in metabolism, rates of energy production, and blood flow. As such, “it is reasonable to speculate that exercise training could be useful to improve functional outcomes in SMA patients,” Alves said.

To investigate the effect of exercise in SMA, researchers in the study evaluated the molecular mechanisms that underlie exercise-induced benefits in a mouse model of SMA.

The results showed that a single bout of exercise was able to increase the full-length expression of SMN in the skeletal muscle of these animals.

SMN2 (the paralog gene of SMN1) produces about 10% of the functional SMN protein. However, the SMN2 gene undergoes a process known as alternative RNA splicing — during which DNA is transformed into a mature RNA molecule — which includes the removal of exon 7, leading to the production of a shorter and less functional SMN protein.

During splicing, introns (the part of the pre-mRNA that does not code for proteins) are removed and exons (the part that does) are joined together. This phenomenon allows for a single gene to give rise to many different proteins.

One of the most important findings in the study was that exercise training increased the inclusion of exon 7 in SMN2 RNA by about 40%. Thus, targeting the inclusion of exon 7 in the SMN transcript is a useful strategy to further increase functional SMN protein levels.

These results strongly suggest that exercise regulates the splicing processes that keep exon 7 retained when transcribing the SMN2 gene.

“The use of exercise protocols as a strategy to increase SMN levels in peripheral tissues foster enthusiasm that exercise might not be 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,” Alves said.