The role of the neuraminidase-1 on muscle atrophy

• Grant number: 11/03857-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2011
• End date: October 31, 2012
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Edmar Zanoteli
• Grantee: Vanessa Rodrigues Rizzato
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Lysosomal neuraminidase (NEU1) is the glycosidase responsible for the catabolism of sialic acid-containing glycoconjugates. A deficiency of this enzyme is associated with the lysosomal storage disease sialidosis. Children affected by this disease have severe systemic and neurological abnormalities, which include muscle hypotonia, atrophy and osteoskeletal deformities. Neu1-/- mice are a close phenocopy of the severe human condition. Histological examination of Neu1-/- muscle reveals 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. In addition, an overt atrophic phenotype has been observed. Nerve sciatic denervation will be realized in normal and Neu1 deficient mice with the objective to verify the histological and ultrastructural effects of muscle atrophy induction. The expression of collagen III, IV and VI will be assessed to detect the presence of collagen deposition and fibrotic formation after denervation. The expression of the gene Neu1 will be studied on normal skeletal muscle during the different moments after denervation to analyze its participation on muscle atrophy process. Considering that the Neu1 participates of the sialic acid regulation of some cathepsins, the cathepsin B and L activity will be analyzed on skeletal muscle from denervated and non denervated mice. The involvement of Neu1 on autophagy process will be investigated by the analysis of the autophagosomes formation at ultrastructural level, acid phosphatase staining and expression of the protein LC3. The determination of Neu1 role on muscle physiology will be the great value to understand the neuromuscular clinical manifestations reported in patients with Neu1 deficiency and the importance of lysosomes and the sialic acid metabolism on the physiopathogenesis of muscle diseases. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

RIZZATO, Vanessa Rodrigues. The role of neuraminidase-1 in muscle atrophy. 2014. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.