Muscle degeneration in neuraminidase 1-deficient mice results from infiltration of the muscle fibers by expanded connective tissue

Abstract

SUMMARY 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.

Dying myofibers in elderly mouse skeletal muscles are characterized by the appearance of dystrophin-encircled vacuoles

“…Similar features have been reported in the myofibers of patients with lysosomal myopathies (Nishino 2006), and in mice with induced defective autophagy (Zanoteli et al 2010), but have not previously been described in normal aged skeletal muscle. DEVILs often contained nuclei or diffuse non-specific AlexaFluor staining, typically characteristic of connective tissue (Fig.…”

“…However, this mode of cell death only appears viable in autophagy competent cells. DEVILated myofibers appeared to resemble the myofiber morphology characteristic of AVMs (Nishino 2006;Zanoteli et al 2010), where the vacuoles and invaginations that define these conditions likely arise from the pathological enlargement of autophagic vacuoles due to autophagic dysfunction. In a number of autophagic myopathies, this often results in the buildup of autophagic substrates such as glycogen and p62.…”

“…DEVILs bear a striking morphological resemblance to the myofibers of AVMs (Danon et al 1981;Nishino 2006;Zanoteli et al 2010) and may therefore be the result of similar physiological dysfunctions. The histochemical features of DEVILs are consistent with some AVMs but not others.…”

Regulated lysosomal exocytosis mediates cancer progression

“…3D). Given that accumulation of oversialylated LAMP1 at the lysosomal membrane was shown to increase the number of lysosomes poised to tether to and dock at the PM (1,7,8,26), we compared the number and intracellular location of lysosomes in both RMS cell lines. .…”

“…−/− mouse model of sialidosis (6), excessive lysosomal exocytosis underlies many of the disease's pathologic manifestations (1,7,8). Specifically, in muscle connective tissue, increased lysosomal exocytosis causes both hyperproliferation of myofibroblasts and excessive deposition and processing of the ECM.…”