BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia

Background and aims: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is require...

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Authors: Fornelli, Claudia, Beltrà, Marc, Zorzano Olarte, Antonio, Costelli, Paola, Sebastián Muñoz, David, Penna, Fabio
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/220113
Online Access:https://hdl.handle.net/2445/220113
Access Level:Open access
Keyword:Càncer
Atròfia muscular
Caquèxia
Autofàgia
Cancer
Muscular atrophy
Cachexia
Autophagy
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oai_identifier_str oai:diposit.ub.edu:2445/220113
network_acronym_str ES
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repository_id_str
spelling BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer CachexiaFornelli, ClaudiaBeltrà, MarcZorzano Olarte, AntonioCostelli, PaolaSebastián Muñoz, DavidPenna, FabioCàncerAtròfia muscularCaquèxiaAutofàgiaCancerMuscular atrophyCachexiaAutophagyBackground and aims: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function. BNIP3, a key mitophagy-related protein, is significantly increased in the muscles of both mice and human cancer hosts. This study aimed to define the potential of mitigating mitophagy via BNIP3 downregulation in preserving mitochondrial integrity, counteracting skeletal muscle loss in experimental cancer cachexia. Methods: Two in vivo gene delivery methods were performed to knock down muscle BNIP3: electroporation of a BNIP3-specific shRNA expression vector or adenovirus injection. Results: The electroporation effectively reduced muscle BNIP3 in healthy mice but was ineffective in C26 tumor-bearing mice. In contrast, adenovirus-mediated BNIP3 knockdown successfully decreased BNIP3 levels also in tumor hosts. Although BNIP3 knockdown did not impact overall on body or muscle mass, it improved muscle fiber size in C26-bearing miceh2, suggesting partial prevention of muscle atrophy. Mitochondrial respiratory chain complexes (OxPhos) and TOM20 protein levels were consistently rescued, indicating improvements in mitochondrial mass, while H2O2 levels were unchanged among the groups, suggesting that BNIP3 downregulation does not impair the endogenous control of oxidative balance. Conclusions: These findings suggest that a fine balance between mitochondrial disposal and biogenesis is fundamental for preserving muscle homeostasis and highlight a potential role for BNIP3 modulation against cancer-induced muscle wasting. Keywords: BNIP3; cancer cachexia; mitochondria; mitophagy; muscle wasting.MDPI2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/220113Articles publicats en revistes (Bioquímica i Fisiologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a https://doi.org/10.3390/cancers16244133Cancers, 2024, vol. 16, num.24https://doi.org/10.3390/cancers16244133cc-by (c) Fornelli, C. et al., 2024http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2201132026-05-27T06:46:51Z
dc.title.none.fl_str_mv BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia
title BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia
spellingShingle BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia
Fornelli, Claudia
Càncer
Atròfia muscular
Caquèxia
Autofàgia
Cancer
Muscular atrophy
Cachexia
Autophagy
title_short BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia
title_full BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia
title_fullStr BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia
title_full_unstemmed BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia
title_sort BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia
dc.creator.none.fl_str_mv Fornelli, Claudia
Beltrà, Marc
Zorzano Olarte, Antonio
Costelli, Paola
Sebastián Muñoz, David
Penna, Fabio
author Fornelli, Claudia
author_facet Fornelli, Claudia
Beltrà, Marc
Zorzano Olarte, Antonio
Costelli, Paola
Sebastián Muñoz, David
Penna, Fabio
author_role author
author2 Beltrà, Marc
Zorzano Olarte, Antonio
Costelli, Paola
Sebastián Muñoz, David
Penna, Fabio
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Càncer
Atròfia muscular
Caquèxia
Autofàgia
Cancer
Muscular atrophy
Cachexia
Autophagy
topic Càncer
Atròfia muscular
Caquèxia
Autofàgia
Cancer
Muscular atrophy
Cachexia
Autophagy
description Background and aims: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function. BNIP3, a key mitophagy-related protein, is significantly increased in the muscles of both mice and human cancer hosts. This study aimed to define the potential of mitigating mitophagy via BNIP3 downregulation in preserving mitochondrial integrity, counteracting skeletal muscle loss in experimental cancer cachexia. Methods: Two in vivo gene delivery methods were performed to knock down muscle BNIP3: electroporation of a BNIP3-specific shRNA expression vector or adenovirus injection. Results: The electroporation effectively reduced muscle BNIP3 in healthy mice but was ineffective in C26 tumor-bearing mice. In contrast, adenovirus-mediated BNIP3 knockdown successfully decreased BNIP3 levels also in tumor hosts. Although BNIP3 knockdown did not impact overall on body or muscle mass, it improved muscle fiber size in C26-bearing miceh2, suggesting partial prevention of muscle atrophy. Mitochondrial respiratory chain complexes (OxPhos) and TOM20 protein levels were consistently rescued, indicating improvements in mitochondrial mass, while H2O2 levels were unchanged among the groups, suggesting that BNIP3 downregulation does not impair the endogenous control of oxidative balance. Conclusions: These findings suggest that a fine balance between mitochondrial disposal and biogenesis is fundamental for preserving muscle homeostasis and highlight a potential role for BNIP3 modulation against cancer-induced muscle wasting. Keywords: BNIP3; cancer cachexia; mitochondria; mitophagy; muscle wasting.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/220113
url https://hdl.handle.net/2445/220113
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a https://doi.org/10.3390/cancers16244133
Cancers, 2024, vol. 16, num.24
https://doi.org/10.3390/cancers16244133
dc.rights.none.fl_str_mv cc-by (c) Fornelli, C. et al., 2024
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Fornelli, C. et al., 2024
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Fisiologia)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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