{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T07:57:45Z","timestamp":1782633465086,"version":"3.54.5"},"reference-count":38,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Spinal Muscular Atrophy (SMA) is a genetic disorder characterized by the progressive loss of motor neurons and consequent muscle atrophy. Although SMN-targeted therapies have significantly improved survival and motor outcomes, residual muscle weakness remains a major clinical challenge, particularly in patients treated later in the disease course. Myostatin, a potent negative regulator of skeletal muscle mass, has emerged as a promising therapeutic target to address this gap. This review summarizes the preclinical and clinical evidence supporting the modulation of the myostatin pathway in SMA. Preclinical studies have demonstrated that inhibiting myostatin, especially when combined with SMN-enhancing agents, can increase muscle mass, improve motor function, and enhance neuromuscular connectivity in SMA mouse models. These findings provide a strong rationale for translating myostatin inhibition into clinical practice as an adjunctive strategy. Early clinical trials investigating myostatin inhibitors have shown favorable safety profiles and preliminary signs of target engagement. However, large-scale trials have yet to demonstrate widespread, robust efficacy across diverse patient populations. Despite this, myostatin pathway inhibition remains a compelling approach, particularly when integrated into broader treatment paradigms aimed at enhancing motor unit stability and function in individuals with SMA. Further clinical research is essential to validate efficacy, determine optimal timing, and define the patient subgroups most likely to benefit from myostatin-targeted therapies.<\/jats:p>","DOI":"10.3390\/ijms26125858","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T06:11:07Z","timestamp":1750313467000},"page":"5858","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Myostatin Modulation in Spinal Muscular Atrophy: A Systematic Review of Preclinical and Clinical Evidence"],"prefix":"10.3390","volume":"26","author":[{"given":"Martina","family":"Gnazzo","sequence":"first","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2730-2791","authenticated-orcid":false,"given":"Giulia","family":"Pisan\u00f2","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5795-5834","authenticated-orcid":false,"given":"Valentina","family":"Baldini","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy"},{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna, 40127 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Giacomelli","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, University Hospital, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Scullin","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, University Hospital, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Piccolo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Child Neuropsychiatry, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4896-1164","authenticated-orcid":false,"given":"Emanuela Claudia","family":"Turco","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Child Neuropsychiatry, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4103-2837","authenticated-orcid":false,"given":"Susanna","family":"Esposito","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, University Hospital, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6777-1721","authenticated-orcid":false,"given":"Maria Carmela","family":"Pera","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Child Neuropsychiatry, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9306","DOI":"10.1073\/pnas.151270098","article-title":"Regulation of myostatin activity and muscle growth","volume":"98","author":"Lee","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/(SICI)1097-4652(199907)180:1<1::AID-JCP1>3.0.CO;2-V","article-title":"Myostatin, a transforming growth factor-\u03b2 superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct","volume":"180","author":"Sharma","year":"1999","journal-title":"J. Cell. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1101\/gr.7.9.910","article-title":"Mutations in myostatin (GDF8) in Double-Muscled Belgian Blue and Piedmontese Cattle","volume":"7","author":"Kambadur","year":"1997","journal-title":"Genome Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1113\/expphysiol.2006.033571","article-title":"Effect of swimming on myostatin expression in white and red gastrocnemius muscle and in cardiac muscle of rats","volume":"91","author":"Matsakas","year":"2006","journal-title":"Exp. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mosher, D.S., Quignon, P., Bustamante, C.D., Sutter, N.B., Mellersh, C.S., Parker, H.G., A Ostrander, E., and Takahashi, J.S. (2007). A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030079"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/ng1810","article-title":"A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep","volume":"38","author":"Clop","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1056\/NEJMoa040933","article-title":"Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child","volume":"350","author":"Schuelke","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1126\/science.1069525","article-title":"Induction of Cachexia in Mice by Systemically Administered Myostatin","volume":"296","author":"Zimmers","year":"2002","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.bbrc.2004.01.085","article-title":"Characterization and identification of the inhibitory domain of GDF-8 propeptide","volume":"315","author":"Jiang","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3125","DOI":"10.2527\/jas.2016-0532","article-title":"INVITED REVIEW: Inhibitors of myostatin as methods of enhancing muscle growth and development1","volume":"94","author":"Chen","year":"2016","journal-title":"J. Anim. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"367","DOI":"10.15252\/embj.201797883","article-title":"Structure of the human myostatin precursor and determinants of growth factor latency","volume":"37","author":"Cotton","year":"2018","journal-title":"EMBO J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7230","DOI":"10.1128\/MCB.23.20.7230-7242.2003","article-title":"Myostatin Signals through a Transforming Growth Factor \u03b2-Like Signaling Pathway to Block Adipogenesis","volume":"23","author":"Rebbapragada","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15842","DOI":"10.1073\/pnas.2534946100","article-title":"Activation of latent myostatin by the BMP-1\/tolloid family of metalloproteinases","volume":"100","author":"Wolfman","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"C195","DOI":"10.1152\/ajpcell.00012.2011","article-title":"Human myostatin negatively regulates human myoblast growth and differentiation","volume":"301","author":"McFarlane","year":"2011","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4361","DOI":"10.1007\/s00018-014-1689-x","article-title":"Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways","volume":"71","author":"Rodriguez","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13023-024-03278-8","article-title":"A horizontal and perpendicular interlaminar approach for intrathecal nusinersen injection in patients with spinal muscular atrophy and scoliosis: An observational study","volume":"19","author":"Huang","year":"2024","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.afos.2023.03.008","article-title":"The elusive role of myostatin signaling for muscle regeneration and maintenance of muscle and bone homeostasis","volume":"9","author":"Mitra","year":"2023","journal-title":"Osteoporos. Sarcopenia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.cellsig.2004.08.003","article-title":"Regulation of GDF-8 signaling by the p38 MAPK","volume":"17","author":"Philip","year":"2004","journal-title":"Cell. Signal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1007\/s11010-024-05120-y","article-title":"Therapeutic applications and challenges in myostatin inhibition for enhanced skeletal muscle mass and functions","volume":"480","author":"Wetzlich","year":"2024","journal-title":"Mol. Cell. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.ncl.2015.07.004","article-title":"Spinal Muscular Atrophy","volume":"33","author":"Kolb","year":"2015","journal-title":"Neurol. Clin."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e209151","DOI":"10.1212\/WNL.0000000000209151","article-title":"Safety and Efficacy of Apitegromab in Patients with Spinal Muscular Atrophy Types 2 and 3","volume":"102","author":"Crawford","year":"2024","journal-title":"Neurology"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Crawford, T.O., Day, J.W., De Vivo, D.C., Krueger, J.M., Mercuri, E., Nascimento, A., Pasternak, A., Mazzone, E.S., Duong, T., and Song, G. (2024). Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: Results from the 36-month TOPAZ study. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1419791"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-021-81669-8","article-title":"Novel myostatin-specific antibody enhances muscle strength in muscle disease models","volume":"11","author":"Muramatsu","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Servais, L., Lair, L.L., Connolly, A.M., Byrne, B.J., Chen, K.S., Coric, V., Qureshi, I., Durham, S., Campbell, D.J., and Maclaine, G. (2024). Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910273"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.recesp.2021.06.016","article-title":"Declaraci\u00f3n PRISMA 2020: Una gu\u00eda actualizada para la publicaci\u00f3n de revisiones sistem\u00e1ticas","volume":"74","author":"Page","year":"2021","journal-title":"Rev. Espanola De Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3203","DOI":"10.1007\/s12325-021-01757-z","article-title":"A Randomized Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Study of the Novel Myostatin Inhibitor Apitegromab (SRK-015): A Potential Treatment for Spinal Muscular Atrophy","volume":"38","author":"Barrett","year":"2021","journal-title":"Adv. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"fcae062","DOI":"10.1093\/braincomms\/fcae062","article-title":"Serum myostatin as a candidate disease severity and progression biomarker of spinal muscular atrophy","volume":"6","author":"Chadanowicz","year":"2024","journal-title":"Brain Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1093\/hmg\/ddv629","article-title":"Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset","volume":"25","author":"Feng","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Liu, M., Hammers, D.W., Barton, E.R., Sweeney, H.L., and Singh, R.N. (2016). Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166803"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1093\/hmg\/ddy382","article-title":"Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy","volume":"28","author":"Long","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Mackels, L., Mariot, V., Buscemi, L., Servais, L., and Dumonceaux, J. (2024). Impact of Disease Severity and Disease-Modifying Therapies on Myostatin Levels in SMA Patients. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168763"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Piemonte, F., Petrillo, S., Capasso, A., Coratti, G., D'AMico, A., Catteruccia, M., Pera, M.C., Palermo, C., Pane, M., and Abiusi, E. (2025). Myostatin Levels in SMA Following Disease-Modifying Treatments: A Multi-Center Study. Ann. Clin. Transl. Neurol.","DOI":"10.1002\/acn3.70070"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.nmd.2011.10.012","article-title":"Transgenic inactivation of murine myostatin does not decrease the severity of disease in a model of Spinal Muscular Atrophy","volume":"22","author":"Rindt","year":"2012","journal-title":"Neuromuscul. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1093\/hmg\/ddn426","article-title":"Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy","volume":"18","author":"Rose","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1177\/10915818211025477","article-title":"Preclinical Safety Assessment and Toxicokinetics of Apitegromab, an Antibody Targeting Proforms of Myostatin for the Treatment of Muscle-Atrophying Disease","volume":"40","author":"Welsh","year":"2021","journal-title":"Int. J. Toxicol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1002\/jcsm.12542","article-title":"Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy","volume":"11","author":"Zhou","year":"2020","journal-title":"J. Cachex- Sarcopenia Muscle"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Vandenbroucke, J.P., von Elm, E., Altman, D.G., G\u00f8tzsche, P.C., Mulrow, C.D., Pocock, S.J., Poole, C., Schlesselman, J.J., Egger, M., and STROBE Initiative (2007). Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and elaboration. Ann. Intern. Med., 147.","DOI":"10.7326\/0003-4819-147-8-200710160-00010-w1"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jclinepi.2015.06.005","article-title":"ROBIS: A new tool to assess risk of bias in systematic reviews was developed","volume":"69","author":"Whiting","year":"2016","journal-title":"J. Clin. Epidemiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5858\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:54:36Z","timestamp":1760032476000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5858"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":38,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26125858"],"URL":"https:\/\/doi.org\/10.3390\/ijms26125858","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,18]]}}}