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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MDPI AG
2019-06-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/6/597 |
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| author | Vanina Romanello Marco Scalabrin Mattia Albiero Bert Blaauw Luca Scorrano Marco Sandri |
| author_facet | Vanina Romanello Marco Scalabrin Mattia Albiero Bert Blaauw Luca Scorrano Marco Sandri |
| author_sort | Vanina Romanello |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T08:36:49Z |
| format | Article |
| id | doaj.art-755944c4df984c3a84fe3ff010816fab |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T08:36:49Z |
| publishDate | 2019-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-755944c4df984c3a84fe3ff010816fab2023-09-02T17:12:57ZengMDPI AGCells2073-44092019-06-018659710.3390/cells8060597cells8060597Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal MusclesVanina Romanello0Marco Scalabrin1Mattia Albiero2Bert Blaauw3Luca Scorrano4Marco Sandri5Veneto Institute of Molecular Medicine, via Orus 2, 35129 Padua, ItalyVeneto Institute of Molecular Medicine, via Orus 2, 35129 Padua, ItalyVeneto Institute of Molecular Medicine, via Orus 2, 35129 Padua, ItalyVeneto Institute of Molecular Medicine, via Orus 2, 35129 Padua, ItalyVeneto Institute of Molecular Medicine, via Orus 2, 35129 Padua, ItalyVeneto Institute of Molecular Medicine, via Orus 2, 35129 Padua, ItalyThe 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.https://www.mdpi.com/2073-4409/8/6/597mitochondrial fusionfissionmitophagyFGF21muscle wastingmuscle dystrophy |
| spellingShingle | Vanina Romanello Marco Scalabrin Mattia Albiero Bert Blaauw Luca Scorrano Marco Sandri Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles Cells mitochondrial fusion fission mitophagy FGF21 muscle wasting muscle dystrophy |
| 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 | mitochondrial fusion fission mitophagy FGF21 muscle wasting muscle dystrophy |
| url | https://www.mdpi.com/2073-4409/8/6/597 |
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