Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy.

Skeletal muscle atrophy is a feature of aging (termed sarcopenia) and various diseases, such as cancer and kidney failure. Effective drug treatment options for muscle atrophy are lacking. The tapeworm medication, niclosamide is being assessed for repurposing to treat numerous diseases, including end...

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Autores principales:	Hyun-Jun Kim, Ji-Hyung Lee, Seon-Wook Kim, Sang-Hoon Lee, Da-Woon Jung, Darren R Williams
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/89c2975d7c574f588b040eb29f9c4a79
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spelling	oai:doaj.org-article:89c2975d7c574f588b040eb29f9c4a792021-12-02T20:05:29ZInvestigation of niclosamide as a repurposing agent for skeletal muscle atrophy.1932-620310.1371/journal.pone.0252135https://doaj.org/article/89c2975d7c574f588b040eb29f9c4a792021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252135https://doaj.org/toc/1932-6203Skeletal muscle atrophy is a feature of aging (termed sarcopenia) and various diseases, such as cancer and kidney failure. Effective drug treatment options for muscle atrophy are lacking. The tapeworm medication, niclosamide is being assessed for repurposing to treat numerous diseases, including end-stage cancer metastasis and hepatic steatosis. In this study, we investigated the potential of niclosamide as a repurposing drug for muscle atrophy. In a myotube atrophy model using the glucocorticoid, dexamethasone, niclosamide did not prevent the reduction in myotube diameter or the decreased expression of phosphorylated FOXO3a, which upregulates the ubiquitin-proteasome pathway of muscle catabolism. Treatment of normal myotubes with niclosamide did not activate mTOR, a major regulator of muscle protein synthesis, and increased the expression of atrogin-1, which is induced in catabolic states. Niclosamide treatment also inhibited myogenesis in muscle precursor cells, enhanced the expression of myoblast markers Pax7 and Myf5, and downregulated the expression of differentiation markers MyoD, MyoG and Myh2. In an animal model of muscle atrophy, niclosamide did not improve muscle mass, grip strength or muscle fiber cross-sectional area. Muscle atrophy is also feature of cancer cachexia. IC50 analyses indicated that niclosamide was more cytotoxic for myoblasts than cancer cells. In addition, niclosamide did not suppress the induction of iNOS, a key mediator of atrophy, in an in vitro model of cancer cachexia and did not rescue myotube diameter. Overall, these results suggest that niclosamide may not be a suitable repurposing drug for glucocorticoid-induced skeletal muscle atrophy or cancer cachexia. Nevertheless, niclosamide may be employed as a compound to study mechanisms regulating myogenesis and catabolic pathways in skeletal muscle.Hyun-Jun KimJi-Hyung LeeSeon-Wook KimSang-Hoon LeeDa-Woon JungDarren R WilliamsPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 5, p e0252135 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hyun-Jun Kim Ji-Hyung Lee Seon-Wook Kim Sang-Hoon Lee Da-Woon Jung Darren R Williams Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy.
description	Skeletal muscle atrophy is a feature of aging (termed sarcopenia) and various diseases, such as cancer and kidney failure. Effective drug treatment options for muscle atrophy are lacking. The tapeworm medication, niclosamide is being assessed for repurposing to treat numerous diseases, including end-stage cancer metastasis and hepatic steatosis. In this study, we investigated the potential of niclosamide as a repurposing drug for muscle atrophy. In a myotube atrophy model using the glucocorticoid, dexamethasone, niclosamide did not prevent the reduction in myotube diameter or the decreased expression of phosphorylated FOXO3a, which upregulates the ubiquitin-proteasome pathway of muscle catabolism. Treatment of normal myotubes with niclosamide did not activate mTOR, a major regulator of muscle protein synthesis, and increased the expression of atrogin-1, which is induced in catabolic states. Niclosamide treatment also inhibited myogenesis in muscle precursor cells, enhanced the expression of myoblast markers Pax7 and Myf5, and downregulated the expression of differentiation markers MyoD, MyoG and Myh2. In an animal model of muscle atrophy, niclosamide did not improve muscle mass, grip strength or muscle fiber cross-sectional area. Muscle atrophy is also feature of cancer cachexia. IC50 analyses indicated that niclosamide was more cytotoxic for myoblasts than cancer cells. In addition, niclosamide did not suppress the induction of iNOS, a key mediator of atrophy, in an in vitro model of cancer cachexia and did not rescue myotube diameter. Overall, these results suggest that niclosamide may not be a suitable repurposing drug for glucocorticoid-induced skeletal muscle atrophy or cancer cachexia. Nevertheless, niclosamide may be employed as a compound to study mechanisms regulating myogenesis and catabolic pathways in skeletal muscle.
format	article
author	Hyun-Jun Kim Ji-Hyung Lee Seon-Wook Kim Sang-Hoon Lee Da-Woon Jung Darren R Williams
author_facet	Hyun-Jun Kim Ji-Hyung Lee Seon-Wook Kim Sang-Hoon Lee Da-Woon Jung Darren R Williams
author_sort	Hyun-Jun Kim
title	Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy.
title_short	Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy.
title_full	Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy.
title_fullStr	Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy.
title_full_unstemmed	Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy.
title_sort	investigation of niclosamide as a repurposing agent for skeletal muscle atrophy.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/89c2975d7c574f588b040eb29f9c4a79
work_keys_str_mv	AT hyunjunkim investigationofniclosamideasarepurposingagentforskeletalmuscleatrophy AT jihyunglee investigationofniclosamideasarepurposingagentforskeletalmuscleatrophy AT seonwookkim investigationofniclosamideasarepurposingagentforskeletalmuscleatrophy AT sanghoonlee investigationofniclosamideasarepurposingagentforskeletalmuscleatrophy AT dawoonjung investigationofniclosamideasarepurposingagentforskeletalmuscleatrophy AT darrenrwilliams investigationofniclosamideasarepurposingagentforskeletalmuscleatrophy
_version_	1718375494164938752

Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy.

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