Myostatin/Smad3 in Spinal Muscular Atrophy: Biomarkers of Disease Severity and Treatment Response
4 affiliations
- 1Neurology 4—Neuroimmunology and Neuromuscular Diseases Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy
- 2Ph.D. Program in Pharmacological Biomolecular Sciences, Experimental and Clinical University of Milan Milan Italy
- 3Developmental Neurology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy
- 4Brain‐Targeted Nanotechnologies (BraiNs) Lab Joint Research Platform—Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy
Abstract
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.
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BibTeX
@article{riolo2026myostatinsmad3,
title = {{Myostatin/Smad3 in Spinal Muscular Atrophy: Biomarkers of Disease Severity and Treatment Response}},
author = {Giorgia Riolo and Claudia Dosi and Stefano Parravicini and Riccardo Zanin and Marta Cheli and Eleonora Giacopuzzi Grigoli and Amalia Canciello and Francesca Andreetta and Riccardo Masson and Silvia Bonanno and Stefania Marcuzzo and Lorenzo Maggi},
journal = {Annals of Clinical and Translational Neurology},
year = {2026},
month = oct,
doi = {10.1002/acn3.70564},
url = {https://doi.org/10.1002/acn3.70564},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Myostatin/Smad3 in Spinal Muscular Atrophy: Biomarkers of Disease Severity and Treatment Response
AU - Giorgia Riolo
AU - Claudia Dosi
AU - Stefano Parravicini
AU - Riccardo Zanin
AU - Marta Cheli
AU - Eleonora Giacopuzzi Grigoli
AU - Amalia Canciello
AU - Francesca Andreetta
AU - Riccardo Masson
AU - Silvia Bonanno
AU - Stefania Marcuzzo
AU - Lorenzo Maggi
PY - 2026
DA - 2026/10/26
JO - Annals of Clinical and Translational Neurology
DO - 10.1002/acn3.70564
UR - https://doi.org/10.1002/acn3.70564
AB - 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.
SN - 2328-9503
ER -