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Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles

The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory r...

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Autores principales: Romanello, Vanina, Scalabrin, Marco, Albiero, Mattia, Blaauw, Bert, Scorrano, Luca, Sandri, Marco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627087/
https://www.ncbi.nlm.nih.gov/pubmed/31208084
http://dx.doi.org/10.3390/cells8060597
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author Romanello, Vanina
Scalabrin, Marco
Albiero, Mattia
Blaauw, Bert
Scorrano, Luca
Sandri, Marco
author_facet Romanello, Vanina
Scalabrin, Marco
Albiero, Mattia
Blaauw, Bert
Scorrano, Luca
Sandri, Marco
author_sort Romanello, Vanina
collection PubMed
description The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of FGF21. However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting. We generated inducible muscle-specific Opa1 and Drp1 double-knockout mice to address the physiological relevance of the concomitant impairment of fusion and fission machinery in skeletal muscle. Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways. This ultimately results in ER stress, muscle loss, and the reduction of force generation. However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness. Thus, the simultaneous inhibition of fusion and fission processes mitigates the detrimental effects of unbalanced mitochondrial fusion and prevents the secretion of pro-senescence factors.
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spelling pubmed-66270872019-07-19 Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles Romanello, Vanina Scalabrin, Marco Albiero, Mattia Blaauw, Bert Scorrano, Luca Sandri, Marco Cells Article The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of FGF21. However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting. We generated inducible muscle-specific Opa1 and Drp1 double-knockout mice to address the physiological relevance of the concomitant impairment of fusion and fission machinery in skeletal muscle. Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways. This ultimately results in ER stress, muscle loss, and the reduction of force generation. However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness. Thus, the simultaneous inhibition of fusion and fission processes mitigates the detrimental effects of unbalanced mitochondrial fusion and prevents the secretion of pro-senescence factors. MDPI 2019-06-15 /pmc/articles/PMC6627087/ /pubmed/31208084 http://dx.doi.org/10.3390/cells8060597 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Romanello, Vanina
Scalabrin, Marco
Albiero, Mattia
Blaauw, Bert
Scorrano, Luca
Sandri, Marco
Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles
title Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles
title_full Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles
title_fullStr Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles
title_full_unstemmed Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles
title_short Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles
title_sort inhibition of the fission machinery mitigates opa1 impairment in adult skeletal muscles
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627087/
https://www.ncbi.nlm.nih.gov/pubmed/31208084
http://dx.doi.org/10.3390/cells8060597
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