Serum Myostatin as a Disease Severity and Progression Biomarker of Spinal Muscular Atrophy

Topic:

Translational Research

Poster Number: S119

Author(s):

Jonas Alex Morales Saute, PhD, Universidade Federal do Rio Grande do Sul, Ana Letícia Amorim de Albuquerque, MD, Graduate Program in Medicine: Medical Sciences, Federal University of Rio Grande do Sul, Porto Aleg, Júlia Kersting Chadanowicz, Clinical Neurogenetics research group, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Giovanna Câmara Giudicelli, PhD, Bioinformatics core, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Ana Lucia Portella Staub, MSc, Clinical Neurogenetics research group, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Arthur Carpeggiani Weber, Clinical Neurogenetics research group, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Jordana Miranda De Souza Silva, PhD, Graduate Program in Medicine: Medical Sciences, Federal University of Rio Grande do Sul, Porto Alegr, Michele Michelin Becker, MD, PhD, Child Neurology Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Thayne Woycinck Kowalski, PhD, Bioinformatics core, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Marina Siebert, PhD, Unit of Laboratorial Research, Experimental Research Center, Hospital de Clínicas de Porto Alegre (H

BACKGROUND: The identification of biomarkers for spinal muscular atrophy (SMA) is crucial for predicting disease progression, severity, and response to new disease-modifying therapies. OBJECTIVE: Investigate the role of serum levels of myostatin and follistatin as biomarkers for SMA, considering muscle atrophy secondary to denervation as the main clinical manifestation of the disease. METHODOLOGY: The study evaluated the differential gene expression of myostatin and follistatin in a lesional model of gastrocnemius denervation in mice, as well as in a meta-analysis of three datasets in transgenic mice models of SMA, and in two studies involving humans with SMA. Subsequently, a case-control study involving 27 SMA patients and 27 controls was conducted, followed by a 12-month cohort study with 25 SMA cases. Serum levels of myostatin and follistatin were analyzed using enzyme-linked immunosorbent assay at a single center in southern Brazil. RESULTS: Skeletal muscle gene expression of myostatin decreased and of follistatin increased following lesional muscle denervation in mice, consistent with findings in the SMA transgenic mice meta-analysis and in the iliopsoas muscle of 5 patients with SMA type 1. Median serum myostatin levels were significantly lower in SMA patients (98 pg/mL; 5-157) compared to controls (412 pg/mL; 299-730) (p<0.001). Lower myostatin levels were associated with greater disease severity based on clinician-rated outcomes (Rho=0.493-0.812; p<0.05). After 12 months, there was a further reduction in myostatin levels among SMA cases (p=0.021). Follistatin levels did not differ between cases and controls, and no significant changes were observed over time. The follistatin:myostatin ratio was significantly increased in SMA subjects and inversely correlated with motor severity. CONCLUSION: Serum myostatin levels show promise as a novel biomarker for evaluating the severity and progression of SMA. The decrease in myostatin levels and the subsequent favorable environment for muscle growth may be attributed to denervation caused by motor neuron dysfunction.