PDF(Pubmed)
Abstract：
The identification of biomarkers for spinal muscular atrophy is crucial for predicting disease progression, severity, and response to new disease-modifying therapies. This study aimed to investigate the role of serum levels of myostatin and follistatin as biomarkers for spinal muscular atrophy, considering muscle atrophy secondary to denervation as the main clinical manifestation of the disease. 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 spinal muscular atrophy, and in two studies involving humans with spinal muscular atrophy. Subsequently, a case-control study involving 27 spinal muscular atrophy patients and 27 controls was conducted, followed by a 12-month cohort study with 25 spinal muscular atrophy cases. Serum levels of myostatin and follistatin were analysed using enzyme-linked immunosorbent assay at a single centre in southern Brazil. Skeletal muscle gene expression of myostatin decreased and of follistatin increased following lesional muscle denervation in mice, consistent with findings in the spinal muscular atrophy transgenic mice meta-analysis and in the iliopsoas muscle of five patients with spinal muscular atrophy type 1. Median serum myostatin levels were significantly lower in spinal muscular atrophy 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 spinal muscular atrophy 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 spinal muscular atrophy subjects and inversely correlated with motor severity. Serum myostatin levels show promise as a novel biomarker for evaluating the severity and progression of spinal muscular atrophy. The decrease in myostatin levels and the subsequent favourable environment for muscle growth may be attributed to denervation caused by motor neuron dysfunction.
摘要：
脊髓性肌萎缩的生物标志物的鉴定对于预测疾病进展至关重要。严重程度,以及对新的疾病改善疗法的反应。本研究旨在探讨血清肌肉生长抑制素和卵泡抑素作为脊髓性肌萎缩症生物标志物的作用。认为继发于神经支配的肌肉萎缩是该病的主要临床表现。该研究评估了小鼠腓肠肌去神经损伤模型中肌肉生长抑制素和卵泡抑素的差异基因表达，以及在脊髓性肌萎缩症转基因小鼠模型的三个数据集的荟萃分析中，以及两项涉及脊髓性肌萎缩症的研究。随后，进行了一项涉及27名脊髓性肌萎缩患者和27名对照的病例对照研究，随后是一项为期12个月的队列研究，包括25例脊髓性肌萎缩病例。在巴西南部的一个中心使用酶联免疫吸附测定法分析了肌肉生长抑制素和卵泡抑素的血清水平。在小鼠病变肌肉去神经支配后，肌肉生长抑制素的骨骼肌基因表达降低，卵泡抑素的表达增加，与脊髓性肌萎缩症转基因小鼠荟萃分析和5例1型脊髓性肌萎缩症患者髂腰肌的研究结果一致。与对照组(412pg/mL;299-730)相比,脊髓性肌萎缩患者的血清肌肉生长抑制素中位数水平(98pg/mL;5-157)显著更低(P<0.001)。根据临床医生评估的结果，较低的肌肉生长抑制素水平与较高的疾病严重程度相关（Rho=0.493-0.812；P<0.05）。12个月后,脊髓性肌萎缩病例中肌肉生长抑制素水平进一步降低(P=0.021).卵泡抑素水平在病例和对照组之间没有差异，并且随着时间的推移没有观察到显著的变化。脊髓性肌萎缩症受试者的卵泡抑素：肌肉生长抑制素比率显着增加，并与运动严重程度成反比。血清肌肉生长抑制素水平有望作为评估脊髓性肌萎缩严重程度和进展的新型生物标志物。肌肉生长抑制素水平的降低以及随后的有利于肌肉生长的环境可能归因于运动神经元功能障碍引起的神经支配。
