Tags

Type your tag names separated by a space and hit enter

Sunitinib promotes myogenic regeneration and mitigates disease progression in the mdx mouse model of Duchenne muscular dystrophy.
Hum Mol Genet. 2019 07 01; 28(13):2120-2132.HM

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 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.

Authors+Show Affiliations

Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA.Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA.Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA.Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA.Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA.Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA.Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA.Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA.Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA.Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA.Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA.Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30806670

Citation

Fontelonga, Tatiana M., et al. "Sunitinib Promotes Myogenic Regeneration and Mitigates Disease Progression in the Mdx Mouse Model of Duchenne Muscular Dystrophy." Human Molecular Genetics, vol. 28, no. 13, 2019, pp. 2120-2132.
Fontelonga TM, Jordan B, Nunes AM, et al. Sunitinib promotes myogenic regeneration and mitigates disease progression in the mdx mouse model of Duchenne muscular dystrophy. Hum Mol Genet. 2019;28(13):2120-2132.
Fontelonga, T. M., Jordan, B., Nunes, A. M., Barraza-Flores, P., Bolden, N., Wuebbles, R. D., Griner, L. M., Hu, X., Ferrer, M., Marugan, J., Southall, N., & Burkin, D. J. (2019). Sunitinib promotes myogenic regeneration and mitigates disease progression in the mdx mouse model of Duchenne muscular dystrophy. Human Molecular Genetics, 28(13), 2120-2132. https://doi.org/10.1093/hmg/ddz044
Fontelonga TM, et al. Sunitinib Promotes Myogenic Regeneration and Mitigates Disease Progression in the Mdx Mouse Model of Duchenne Muscular Dystrophy. Hum Mol Genet. 2019 07 1;28(13):2120-2132. PubMed PMID: 30806670.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sunitinib promotes myogenic regeneration and mitigates disease progression in the mdx mouse model of Duchenne muscular dystrophy. AU - Fontelonga,Tatiana M, AU - Jordan,Brennan, AU - Nunes,Andreia M, AU - Barraza-Flores,Pamela, AU - Bolden,Nicholas, AU - Wuebbles,Ryan D, AU - Griner,Lesley Mathews, AU - Hu,Xin, AU - Ferrer,Marc, AU - Marugan,Juan, AU - Southall,Noel, AU - Burkin,Dean J, PY - 2018/11/27/received PY - 2019/01/28/revised PY - 2019/02/18/accepted PY - 2019/2/27/pubmed PY - 2020/3/31/medline PY - 2019/2/27/entrez SP - 2120 EP - 2132 JF - Human molecular genetics JO - Hum Mol Genet VL - 28 IS - 13 N2 - 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. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/30806670/Sunitinib_promotes_myogenic_regeneration_and_mitigates_disease_progression_in_the_mdx_mouse_model_of_Duchenne_muscular_dystrophy_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddz044 DB - PRIME DP - Unbound Medicine ER -