Myostatin/Smad3 in Spinal Muscular Atrophy: Biomarkers of Disease Severity and Treatment Response

OBJECTIVE: Given the role of Myostatin (MSTN) in muscle homeostasis and its modulation by current spinal muscular atrophy (SMA) therapies, we investigated serum MSTN and, for the first time, its downstream effector Smad3 as candidate non-invasive biomarkers in SMA patients undergoing disease-modifying therapies (DMTs). METHODS: The study included pediatric and adult SMA patients receiving DMTs (Nusinersen = 15; Risdiplam = 15), and participants in anti-MSTN clinical trials (n = 7), whose data were analyzed only at baseline. Serum MSTN and Smad3 levels were quantified by ELISA at baseline, 6 and 14 months post-treatment in pediatric and adult SMA patients, respectively, considering the slower DMTs effects in adulthood. RESULTS: Baseline MSTN levels were significantly (p-value < 0.05) higher in: males (915.0 ± 592.5 pg/mL) vs. females (593.4 ± 231.4 pg/mL); SMA III (952.2 ± 598.9 pg/mL) vs. II (541.1 ± 326.4 pg/mL), and walkers (1047.6 ± 548.9 pg/mL) vs. non-sitters (374.6 ± 188.5 pg/mL). Smad3 showed no correlation and remained stable during treatment. In adults MSTN levels positively correlated with Hammersmith Functional Motor Scale Expanded (HFMSE) at baseline (p = 0.01) and post-treatment (p = 0.003). Smad3 levels negatively correlated with baseline HFMSE (p = 0.03) and post-treatment Revised Upper Limb Module scores (p = 0.03). In pediatric patients, MSTN fold change (i.e., post-/pre-therapy ratio) at baseline negatively correlated with HFMSE changes (p = 0.008). INTERPRETATION: MSTN levels were associated with clinical phenotype and motor function, supporting its role as a candidate biomarker of SMA severity in adult and pediatric patients. Our findings also suggest that MSTN may serve as a potential dynamic biomarker of disease progression in pediatric patients, regardless of treatment. Further validation in independent cohorts is warranted.