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J Neuropathol Exp Neurol. 2010 Jun;69(6):643-53. doi: 10.1097/NEN.0b013e3181e0d01c.

Role of thrombospondin 1 in macrophage inflammation in dysferlin myopathy.

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Servei de Neurologia i Laboratori de Neurologia Experimental, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain.


Muscle inflammation can be a prominent feature in several muscular dystrophies. In dysferlin myopathy, it is mainly composed of macrophages. To understand the origin of inflammation in dysferlin-deficient muscle, we analyzed soluble factors involved in monocyte chemotaxis released by myoblasts and myotubes from control and dysferlinopathy patients using a transwell system. Dysferlin-deficient myotubes released more soluble factors involved in monocyte chemotaxis compared with controls (p < 0.001). Messenger RNA microarray analysis showed a 3.2-fold increase of thrombospondin 1 (TSP-1) expression in dysferlin-deficient myotubes. Retrotranscriptasepolymerase chain reaction analysis, ELISA, and immunohistochemistry confirmed these results. Dysferlin mRNA knockdown with short-interfering RNA in normal myogenic cells resulted in TSP-1 mRNA upregulation and increased chemotaxis. Furthermore, monocyte chemotaxis was decreased when TSP-1 was blocked by specific antibodies. In muscle biopsies from dysferlinopathy patients, TSP-1 expression was increased in muscle fibers but not in biopsies of patientswith other myopathies with inflammation; TSP-1 was seen in some macrophages in all samples analyzed. Taken together, the data demonstrate that dysferlin-deficient muscle upregulates TSP-1 in vivoand in vitro and indicate that endogenous chemotactic factors arecrucial to the sustained inflammatory process observed in dysferlinopathies.

[Indexed for MEDLINE]

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