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

Autor:	Fontelonga TM; Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA., Jordan B; Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA., Nunes AM; Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA., Barraza-Flores P; Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA., Bolden N; Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA., Wuebbles RD; Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA., Griner LM; Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA., Hu X; Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA., Ferrer M; Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA., Marugan J; Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA., Southall N; Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA., Burkin DJ; Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2019 Jul 01; Vol. 28 (13), pp. 2120-2132.
DOI:	10.1093/hmg/ddz044
Abstrakt:	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 extracellular matrix. The decreased myofiber damage translated into a significant increase in muscle force production. This study identifies an already FDA-approved compound, Sunitinib, as a possible DMD therapeutic with the potential to treat other muscular dystrophies in which there is defective muscle repair. (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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