The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo

Abstract Acute ischemia–reperfusion injury in skeletal muscle is a significant clinical concern in the trauma setting. The mitochondrial permeability transition inhibitor NIM-811 has previously been shown to reduce ischemic injury in the liver and kidney. The effects of this treatment on skeletal mu...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Khairat Bahgat Youssef El Baradie, Mohammad B. Khan, Bharati Mendhe, Jennifer Waller, Frederick O’Brien, Mark W. Hamrick
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4333496b0887462d908d7302927ea025
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:4333496b0887462d908d7302927ea025
record_format	dspace
spelling	oai:doaj.org-article:4333496b0887462d908d7302927ea0252021-12-02T13:17:42ZThe cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo10.1038/s41598-021-85753-x2045-2322https://doaj.org/article/4333496b0887462d908d7302927ea0252021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85753-xhttps://doaj.org/toc/2045-2322Abstract Acute ischemia–reperfusion injury in skeletal muscle is a significant clinical concern in the trauma setting. The mitochondrial permeability transition inhibitor NIM-811 has previously been shown to reduce ischemic injury in the liver and kidney. The effects of this treatment on skeletal muscle are, however, not well understood. We first used an in vitro model of muscle cell ischemia in which primary human skeletal myoblasts were exposed to hypoxic conditions (1% O2 and 5% CO2) for 6 h. Cells were treated with NIM-811 (0–20 µM). MTS assay was used to quantify cell survival and LDH assay to quantify cytotoxicity 2 h after treatment. Results indicate that NIM-811 treatment of ischemic myotubes significantly increased cell survival and decreased LDH in a dose-dependent manner. We then examined NIM-811 effects in vivo using orthodontic rubber bands (ORBs) for 90 min of single hindlimb ischemia. Mice received vehicle or NIM-811 (10 mg/kg BW) 10 min before reperfusion and 3 h later. Ischemia and reperfusion were monitored using laser speckle imaging. In vivo data demonstrate that mice treated with NIM-811 showed increased gait speed and improved Tarlov scores compared to vehicle-treated mice. The ischemic limbs of female mice treated with NIM-811 showed significantly lower levels of MCP-1, IL-23, IL-6, and IL-1α compared to limbs of vehicle-treated mice. Similarly, male mice treated with NIM-811 showed significantly lower levels of MCP-1 and IL-1a. These findings are clinically relevant as MCP-1, IL-23, IL-6, and IL-1α are all pro-inflammatory factors that are thought to contribute directly to tissue damage after ischemic injury. Results from the in vitro and in vivo experiments suggest that NIM-811 and possibly other mitochondrial permeability transition inhibitors may be effective for improving skeletal muscle salvage and survival after ischemia–reperfusion injury.Khairat Bahgat Youssef El BaradieMohammad B. KhanBharati MendheJennifer WallerFrederick O’BrienMark W. HamrickNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Khairat Bahgat Youssef El Baradie Mohammad B. Khan Bharati Mendhe Jennifer Waller Frederick O’Brien Mark W. Hamrick The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo
description	Abstract Acute ischemia–reperfusion injury in skeletal muscle is a significant clinical concern in the trauma setting. The mitochondrial permeability transition inhibitor NIM-811 has previously been shown to reduce ischemic injury in the liver and kidney. The effects of this treatment on skeletal muscle are, however, not well understood. We first used an in vitro model of muscle cell ischemia in which primary human skeletal myoblasts were exposed to hypoxic conditions (1% O2 and 5% CO2) for 6 h. Cells were treated with NIM-811 (0–20 µM). MTS assay was used to quantify cell survival and LDH assay to quantify cytotoxicity 2 h after treatment. Results indicate that NIM-811 treatment of ischemic myotubes significantly increased cell survival and decreased LDH in a dose-dependent manner. We then examined NIM-811 effects in vivo using orthodontic rubber bands (ORBs) for 90 min of single hindlimb ischemia. Mice received vehicle or NIM-811 (10 mg/kg BW) 10 min before reperfusion and 3 h later. Ischemia and reperfusion were monitored using laser speckle imaging. In vivo data demonstrate that mice treated with NIM-811 showed increased gait speed and improved Tarlov scores compared to vehicle-treated mice. The ischemic limbs of female mice treated with NIM-811 showed significantly lower levels of MCP-1, IL-23, IL-6, and IL-1α compared to limbs of vehicle-treated mice. Similarly, male mice treated with NIM-811 showed significantly lower levels of MCP-1 and IL-1a. These findings are clinically relevant as MCP-1, IL-23, IL-6, and IL-1α are all pro-inflammatory factors that are thought to contribute directly to tissue damage after ischemic injury. Results from the in vitro and in vivo experiments suggest that NIM-811 and possibly other mitochondrial permeability transition inhibitors may be effective for improving skeletal muscle salvage and survival after ischemia–reperfusion injury.
format	article
author	Khairat Bahgat Youssef El Baradie Mohammad B. Khan Bharati Mendhe Jennifer Waller Frederick O’Brien Mark W. Hamrick
author_facet	Khairat Bahgat Youssef El Baradie Mohammad B. Khan Bharati Mendhe Jennifer Waller Frederick O’Brien Mark W. Hamrick
author_sort	Khairat Bahgat Youssef El Baradie
title	The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo
title_short	The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo
title_full	The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo
title_fullStr	The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo
title_full_unstemmed	The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo
title_sort	cyclophilin inhibitor nim-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4333496b0887462d908d7302927ea025
work_keys_str_mv	AT khairatbahgatyoussefelbaradie thecyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT mohammadbkhan thecyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT bharatimendhe thecyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT jenniferwaller thecyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT frederickobrien thecyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT markwhamrick thecyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT khairatbahgatyoussefelbaradie cyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT mohammadbkhan cyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT bharatimendhe cyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT jenniferwaller cyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT frederickobrien cyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo AT markwhamrick cyclophilininhibitornim811increasesmusclecellsurvivalwithhypoxiainvitroandimprovesgaitperformancefollowingischemiareperfusioninvivo
_version_	1718393328150511616

The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo

Ejemplares similares