The respiratory muscles of patients with spinal muscular atrophy: The role of fatigability, disease-modifying therapies, and training

Background
SMA is a severe genetic neuromuscular disease caused by a mutation in the SMN1 gene, resulting in reduced survival motor neuron protein and subsequent degeneration of spinal motor neurons. This leads to progressive muscle weakness affecting the limb, trunk, and respiratory muscles. Respiratory muscle weakness is a major cause of morbidity and mortality in SMA, particularly due to impaired cough efficiency, mucus retention, and respiratory failure. In addition to respiratory muscle weakness, respiratory dysfunction in SMA may be caused by increased respiratory muscle fatigability.

Respiratory muscle fatigability
To assess respiratory muscle fatigability, 55 participants with SMA types 2 and 3 performed a respiratory endurance test (RET) at 20–70% of their maximal inspiratory pressure. Fatigability was defined as the inability to complete 60 consecutive breaths. Fatigability occurred most frequently at 55% load, comparable to healthy individuals (60%), but higher than in Duchenne muscular dystrophy (35%). Thus, individuals with SMA demonstrated normal respiratory muscle fatigability, without transient respiratory muscle weakness and increased perceived fatigue, suggesting an atypical physiological response to fatigue.

Electromyography analysis
Surface electromyography (sEMG) was used to measure muscle activity and fatigue responses of the diaphragm, intercostal, and scalene muscles during the RET. The relative activity of the diaphragm at onset of the RET remained stable at higher intensity levels, while the activity of the intercostal and scalene muscles became more variable. The diaphragm showed the most significant signs of fatigue in participants with fatigability, in contrast to the accessory muscles and participants without fatigability. These findings suggest that the load of breathing against resistance is shared amongst different respiratory muscles.

Effect of disease-modifying therapies
A systematic review summarized 19 studies (384 participants) on the effects of Nusinersen and Risdiplam on lung function and respiratory muscle strength in SMA types 1–4. Most studies showed no significant improvement in respiratory outcomes after 2 to >12 months of treatment. However, Nusinersen appeared to stabilize pulmonary function and respiratory strength—a meaningful therapeutic effect given the natural decline in untreated SMA.

Respiratory muscle training (RESISTANT-study)
The RESISTANT-study evaluated a 12-month respiratory muscle training protocol in 30 participants with SMA and respiratory muscle weakness. Participants trained 10 times a week with individualized resistance. After four months, inspiratory strength increased by 11.8 cmH₂O in the training group (started training at 30% of their maximum) and 6.1 cmH₂O in controls (started training at 10% of their maximum); after 12 months, both groups improved further (+13.5 and +19 cmH₂O). Gains were strongly correlated with training volume. The training was safe, and participants were motivated to continue, though adherence was moderate and improved with physiotherapist supervision.

Conclusions
This thesis demonstrates that individuals with SMA exhibit normal inspiratory muscle fatigability but altered physiological and perceptual responses to fatigue. The diaphragm is the primary site of fatigue during sustained breathing tasks. Current disease-modifying therapies stabilize rather than improve respiratory muscle performance. Importantly, respiratory muscle training is safe, feasible, and effective in enhancing inspiratory strength, particularly when resistance is increased based on perceived exertion and supported by supervised sessions.