Sunitinib promotes myogenic regeneration and mitigates disease progression in the mdx mouse model of Duchenne muscular dystrophy

Human Molecular Genetics
Tatiana M FontelongaDean J Burkin

Abstract

Duchenne muscular dystrophy (DMD) is a lethal, muscle degenerative disease causing premature death of affected children. DMD is characterized by mutations in the dystrophin gene that result in a loss of the dystrophin protein. Loss of dystrophin causes an associated reduction in proteins of the dystrophin glycoprotein complex, leading to contraction-induced sarcolemmal weakening, muscle tearing, fibrotic infiltration and rounds of degeneration and failed regeneration affecting satellite cell populations. The α7β1 integrin has been implicated in increasing myogenic capacity of satellite cells, therefore restoring muscle viability, increasing muscle force and preserving muscle function in dystrophic mouse models. In this study, we show that a Food and Drug Administration (FDA)-approved small molecule, Sunitinib, is a potent α7 integrin enhancer capable of promoting myogenic regeneration by stimulating satellite cell activation and increasing myofiber fusion. Sunitinib exerts its regenerative effects via transient inhibition of SHP-2 and subsequent activation of the STAT3 pathway. Treatment of mdx mice with Sunitinib demonstrated decreased membrane leakiness and damage owing to myofiber regeneration and enhanced support at the ext...Continue Reading

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Citations

Dec 6, 2019·International Journal of Molecular Sciences·Libero VitielloMarcella Canton
Jun 4, 2020·Journal of Vector Ecology : Journal of the Society for Vector Ecology·Peter I WhelanVicki Krause
Mar 3, 2020·Frontiers in Molecular Neuroscience·Pamela Barraza-FloresDean J Burkin
Oct 21, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Eri SasakiYoichi Negishi

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