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

Giulio Ghersi, Erik J. Bonten, Edmar Zanoteli, Alessandra D'Azzo, Linda Mann, A. John Harris, Diantha Van De Vlekkert, Elida M. Gomero, Huimin Hu

Risultato della ricerca: Article

27 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)659-672
Numero di pagine14
RivistaBIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE
Volume1802
Stato di pubblicazionePublished - 2010

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Mucolipidoses
Connective Tissue
Extracellular Matrix
Muscles
Neuraminidase
Neuromuscular Manifestations
Skeletal Muscle
Fibroblasts
Cathepsins
Sarcolemma
Muscle Hypotonia
Metalloproteases
Muscular Diseases
Lysosomes
Age of Onset
Collagen
Animal Models
Cell Proliferation
Pathology
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

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Muscle degeneration in neuramindase 1 deficient mice results from infiltration of the muscle fibers by expanded connective tissue. / Ghersi, Giulio; Bonten, Erik J.; Zanoteli, Edmar; D'Azzo, Alessandra; Mann, Linda; Harris, A. John; De Vlekkert, Diantha Van; Gomero, Elida M.; Hu, Huimin.

In: BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE, Vol. 1802, 2010, pag. 659-672.

Risultato della ricerca: Article

Ghersi, G, Bonten, EJ, Zanoteli, E, D'Azzo, A, Mann, L, Harris, AJ, De Vlekkert, DV, Gomero, EM & Hu, H 2010, 'Muscle degeneration in neuramindase 1 deficient mice results from infiltration of the muscle fibers by expanded connective tissue', BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE, vol. 1802, pagg. 659-672.
Ghersi, Giulio ; Bonten, Erik J. ; Zanoteli, Edmar ; D'Azzo, Alessandra ; Mann, Linda ; Harris, A. John ; De Vlekkert, Diantha Van ; Gomero, Elida M. ; Hu, Huimin. / Muscle degeneration in neuramindase 1 deficient mice results from infiltration of the muscle fibers by expanded connective tissue. In: BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE. 2010 ; Vol. 1802. pagg. 659-672.
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abstract = "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.",
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AU - Ghersi, Giulio

AU - Bonten, Erik J.

AU - Zanoteli, Edmar

AU - D'Azzo, Alessandra

AU - Mann, Linda

AU - Harris, A. John

AU - De Vlekkert, Diantha Van

AU - Gomero, Elida M.

AU - Hu, Huimin

PY - 2010

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N2 - 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.

AB - 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.

KW - NEU1; Sialidosis; Metalloproteinase; Muscle biopsy; Lysosome; ECM

UR - http://hdl.handle.net/10447/50885

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JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

SN - 0925-4439

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