ALL PARTS OF THE MOTOR UNIT MATTER

Effective movement requires uninterrupted function of the entire motor unit—from the motor neuron cell body, along its axon, through the neuromuscular junction, to innervated muscle fibers.

Disruptions along this pathway can lead to weakness and atrophy.^18–21

Lyza, 23

Living with SMA and advocating for progress

MUSCLE: A CRITICAL CONTRIBUTOR TO SMA

In addition to the degradation of motor neurons, muscle wasting is central to the pathology of SMA.^22,23 The overall burden of SMA for children and adults living with the disease is closely linked to functional deficits resulting from hypotonia and the loss of muscle.⁶

Research also suggests that a loss of SMN in skeletal muscle can have a direct impact, resulting in both cell- and non-cell-autonomous defects, such as central nucleation of myofibers, altered regeneration, and dysfunctional myogenesis.²²

Lyza, 23

Living with SMA and advocating for progress

Modern intervention should consider the entire motor unit to adequately treat neuromuscular dysfunction.^2,3

THE MUSCLE
MOSAIC

Despite progressive muscle wasting, people with SMA have some remaining intact muscle.^3,20,24,25

Not all muscle fibers are equally affected by SMA. Some motor neurons maintain synaptic connections, preserving associated muscle fibers.^3,20,24,25 Muscle biopsies in SMA consistently show a mosaic pattern: some fibers appear normal or even hypertrophic, while others are atrophic. This patchiness results from variable rates of denervation and ability of some motor units to compensate or persist longer than others.^26,27

Individual motor neurons are affected differently, and atrophy is not uniform across muscle groups in individuals living with SMA.^20,26

A unique opportunity exists to explore muscle-focused approaches to SMA treatment.

Putting the Muscle in Neuromuscular

At the end of the motor neuron is a muscle that helps enable movement.²⁰ SMN-targeted treatments were designed to address the motor neuron component of the disease and do not directly address the muscle.^1,3

The Path Between Motor Neuron and Muscle

MOTOR NEURON

Illustration of a motor unit with a highlight representing neuromuscular junction

Illustration of a motor unit with a highlight representing muscle fiber

LEARN MORE ABOUT A POTENTIAL TARGET IN SMA TO ADDRESS MUSCLE DYSFUNCTION

LEARN ABOUT MYOSTATIN

References

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Abati E, Manini A, Comi GP, Corti S. Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases. Cell Mol Life Sci. 2022;79(7):374.
Day JW, Howell K, Place A, et al. Advances and limitations for the treatment of spinal muscular atrophy. BMC Pediatr. 2022;22(1):632.
Gnazzo M, Pisanò G, Baldini V, et al. Myostatin modulation in spinal muscular atrophy: A systematic review of preclinical and clinical evidence. Int J Mol Sci. 2025;26(12).
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Finkel RS, Farrar MA, Saito K, et al. Final Safety and Efficacy Data From the SHINE Study in Participants With Infantile-Onset and Later-Onset SMA. Poster presented at: Annual Cure SMA Research and Clinical Care Meeting; June 2024; Austin, TX.
Servais L, Oskoui M, Day J, et al. SUNFISH Parts 1 and 2: 4-year Efficacy and Safety Data of Risdiplam in Types 2 and 3 Spinal Muscular Atrophy (SMA). Poster presented at: Muscular Dystrophy Association (MDA) Clinical and Scientific Conference; March 2025; Dallas, TX.
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A Study for Participants With Spinal Muscular Atrophy (SMA) Who Previously Participated in Nusinersen (ISIS 396443) Investigational Studies (SHINE). ClinicalTrials.gov identifier: NCT02594124. Updated September 27, 2024. Accessed December 10, 2025. https://clinicaltrials.gov/study/NCT02594124
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