Thrombospondin-1 and disease progression in dysferlinopathy

Norifumi Urao, Rita E. Mirza, Thomas F. Corbiere, Zsuzsanna Hollander, Christoph H. Borchers, Timothy J. Koh

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

The purpose of this study was to determine whether thrombospondin (TSP)-1 promotes macrophage activity and disease progression in dysferlinopathy. First, we found that levels of TSP-1 are elevated in blood of non-ambulant dysferlinopathy patients compared with ambulant patients and healthy controls, supporting the idea that TSP-1 levels are correlated with disease progression. We then crossed dysferlinopathic BlaJ mice with TSP-1 knockout mice and assessed disease progression longitudinally with magnetic resonance imaging (MRI). In these mice, deletion of TSP-1 ameliorated loss in volume and mass of the moderately affected gluteal muscle but not of the severely affected psoas muscle. T2 MRI parameters revealed that loss of TSP-1 modestly inhibited inflammation only in gluteal muscle of male mice. Histological assessment indicated that deletion of TSP-1 reduced inflammatory cell infiltration of muscle fibers, but only early in disease progression. In addition, flow cytometry analysis revealed that, in males, TSP-1 knockout reduced macrophage infiltration and phagocytic activity, which is consistent with TSP-1-enhanced phagocytosis and pro-inflammatory cytokine induction in cultured macrophages. In summary, TSP-1 appears to play an accessory role in modulating Mp activity in BlaJ mice in a gender, age and muscle-dependent manner, but is unlikely a primary driver of disease progression of dysferlinopathy.

Original languageEnglish
Pages (from-to)4951-4960
Number of pages10
JournalHuman Molecular Genetics
Volume26
Issue number24
DOIs
Publication statusPublished - Dec 2017
Externally publishedYes

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