Muscle degeneration in neuraminidase 1-deficient mice results from infiltration of the muscle fibers by expanded connective tissue.
Muscle degeneration in neuraminidase 1-deficient mice results from infiltration of the muscle fibers by expanded connective tissue.
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神经氨酸酶 1 缺陷小鼠的肌肉变性是由于扩张的结缔组织浸润肌肉纤维造成的。
DOI：
10.1016/j.bbadis.2010.04.002
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
d'Azzo,Alessandra
中科院分区：
文献类型：
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作者：
Zanoteli,Edmar;vandeVlekkert,Diantha;Bonten,ErikJ;Hu,Huimin;Mann,Linda;Gomero,ElidaM;Harris,AJohn;Ghersi,Giulio;d'Azzo,Alessandra
神经氨酸酶1 （NEU1）调节溶酶体唾液糖缀合物的分解代谢。儿童先天性NEU1缺乏是唾液中毒的基础，唾液中毒是一种严重的神经躯体疾病，患者在发病年龄和严重程度上有广泛的临床表现。骨骨骼畸形和肌肉张力低下已被描述为唾液中毒患者。在这里，我们提出了与小鼠Neu1功能丧失相关的骨骼肌病理的第一个综合分析。在该动物模型中，骨骼肌表现为膜外膜和膜周间隙的扩张，并伴有成纤维细胞样细胞的增殖和胶原的异常沉积。位于扩张结缔组织附近的肌纤维肌膜广泛内陷，导致成纤维细胞样细胞和细胞外基质浸润纤维，并使其细胞质逐渐碎裂。扩张的结缔组织和并置的浸润肌纤维溶酶体标志物均呈强阳性，溶酶体组织蛋白酶和金属蛋白酶的蛋白水解活性均增加。这些综合特征可能导致细胞外基质的异常重塑，这可能导致肌层内陷和进行性肌纤维变性，最终导致明显的萎缩表型。这种独特的肌肉损伤模式，从未在任何肌病中被描述过，可能解释了II型严重唾液中毒患者的神经肌肉表现。更广泛地说，这些发现指出NEU1在细胞增殖和细胞外基质重塑中的潜在作用。
Neuraminidase 1 (NEU1) regulates the catabolism of sialoglycoconjugates in lysosomes. Congenital NEU1 deficiency in children is the basis of sialidosis, a severe neurosomatic disorder in which patients experience a broad spectrum of clinical manifestations varying in the age of onset and severity. Osteoskeletal deformities and muscle hypotonia have been described in patients with sialidosis. Here we present the first comprehensive analysis of the skeletal muscle pathology associated with loss of Neu1 function in mice. In this animal model, skeletal muscles showed an expansion of the epimysial and perimysial spaces, associated with proliferation of fibroblast-like cells and abnormal deposition of collagens. Muscle fibers located adjacent to the expanded connective tissue underwent extensive invagination of their sarcolemma, which resulted in the infiltration of the fibers by fibroblast-like cells and extracellular matrix, and in their progressive cytosolic fragmentation. Both the expanded connective tissue and the juxtaposed infiltrated muscle fibers were strongly positive for lysosomal markers and displayed increased proteolytic activity of lysosomal cathepsins and metalloproteinases. These combined features could lead to abnormal remodeling of the extracellular matrix that could be responsible for sarcolemmal invagination and progressive muscle fiber degeneration, ultimately resulting in an overt atrophic phenotype. This unique pattern of muscle damage, which has never been described in any myopathy, might explain the neuromuscular manifestations reported in patients with the type II severe form of sialidosis. More broadly, these findings point to a potential role of NEU1 in cell proliferation and extracellular matrix remodeling.