Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates
Abstract Tubular aggregates (TA) are honeycomb-like arrays of sarcoplasmic-reticulum (SR) tubules affecting aged glycolytic fibers of male individuals and inducing severe sarcomere disorganization and muscular pain. TA develop in skeletal muscle from Tubular Aggregate Myopathy (TAM) patients as well...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05016-z |
| _version_ | 1811334634975264768 |
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| author | Cristina Sánchez-González Juan Cruz Herrero Martín Beñat Salegi Ansa Cristina Núñez de Arenas Brina Stančič Marta P. Pereira Laura Contreras José M. Cuezva Laura Formentini |
| author_facet | Cristina Sánchez-González Juan Cruz Herrero Martín Beñat Salegi Ansa Cristina Núñez de Arenas Brina Stančič Marta P. Pereira Laura Contreras José M. Cuezva Laura Formentini |
| author_sort | Cristina Sánchez-González |
| collection | DOAJ |
| description | Abstract Tubular aggregates (TA) are honeycomb-like arrays of sarcoplasmic-reticulum (SR) tubules affecting aged glycolytic fibers of male individuals and inducing severe sarcomere disorganization and muscular pain. TA develop in skeletal muscle from Tubular Aggregate Myopathy (TAM) patients as well as in other disorders including endocrine syndromes, diabetes, and ageing, being their primary cause unknown. Nowadays, there is no cure for TA. Intriguingly, both hypoxia and calcium dyshomeostasis prompt TA formation, pointing to a possible role for mitochondria in their setting. However, a functional link between mitochondrial dysfunctions and TA remains unknown. Herein, we investigate the alteration in muscle-proteome of TAM patients, the molecular mechanism of TA onset and a potential therapy in a preclinical mouse model of the disease. We show that in vivo chronic inhibition of the mitochondrial ATP synthase in muscle causes TA. Upon long-term restrained oxidative phosphorylation (OXPHOS), oxidative soleus experiments a metabolic and structural switch towards glycolytic fibers, increases mitochondrial fission, and activates mitophagy to recycle damaged mitochondria. TA result from the overresponse of the fission controller DRP1, that upregulates the Store-Operate-Calcium-Entry and increases the mitochondria-SR interaction in a futile attempt to buffer calcium overloads upon prolonged OXPHOS inhibition. Accordingly, hypoxic muscles cultured ex vivo show an increase in mitochondria/SR contact sites and autophagic/mitophagic zones, where TA clusters grow around defective mitochondria. Moreover, hypoxia triggered a stronger TA formation upon ATP synthase inhibition, and this effect was reduced by the DRP1 inhibitor mDIVI. Remarkably, the muscle proteome of TAM patients displays similar alterations in mitochondrial dynamics and in ATP synthase contents. In vivo edaravone treatment in mice with restrained OXPHOS restored a healthy phenotype by prompting mitogenesis and mitochondrial fusion. Altogether, our data provide a functional link between the ATP synthase/DRP1 axis and the setting of TA, and repurpose edaravone as a possible treatment for TA-associated disorders. |
| first_indexed | 2024-04-13T17:11:58Z |
| format | Article |
| id | doaj.art-866b5a1abae84696bab7d38a4dac2212 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T17:11:58Z |
| publishDate | 2022-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-866b5a1abae84696bab7d38a4dac22122022-12-22T02:38:15ZengNature Publishing GroupCell Death and Disease2041-48892022-06-0113611510.1038/s41419-022-05016-zChronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregatesCristina Sánchez-González0Juan Cruz Herrero Martín1Beñat Salegi Ansa2Cristina Núñez de Arenas3Brina Stančič4Marta P. Pereira5Laura Contreras6José M. Cuezva7Laura Formentini8Departamento de Biología Molecular, Centro de Biología Molecular ‘“Severo Ochoa’” (CBMSO), c/ Nicolás Cabrera 1, Universidad Autónoma de MadridDepartamento de Biología Molecular, Centro de Biología Molecular ‘“Severo Ochoa’” (CBMSO), c/ Nicolás Cabrera 1, Universidad Autónoma de MadridDepartamento de Biología Molecular, Centro de Biología Molecular ‘“Severo Ochoa’” (CBMSO), c/ Nicolás Cabrera 1, Universidad Autónoma de MadridDepartamento de Biología Molecular, Centro de Biología Molecular ‘“Severo Ochoa’” (CBMSO), c/ Nicolás Cabrera 1, Universidad Autónoma de MadridDepartamento de Biología Molecular, Centro de Biología Molecular ‘“Severo Ochoa’” (CBMSO), c/ Nicolás Cabrera 1, Universidad Autónoma de MadridDepartamento de Biología Molecular, Centro de Biología Molecular ‘“Severo Ochoa’” (CBMSO), c/ Nicolás Cabrera 1, Universidad Autónoma de MadridDepartamento de Biología Molecular, Centro de Biología Molecular ‘“Severo Ochoa’” (CBMSO), c/ Nicolás Cabrera 1, Universidad Autónoma de MadridDepartamento de Biología Molecular, Centro de Biología Molecular ‘“Severo Ochoa’” (CBMSO), c/ Nicolás Cabrera 1, Universidad Autónoma de MadridDepartamento de Biología Molecular, Centro de Biología Molecular ‘“Severo Ochoa’” (CBMSO), c/ Nicolás Cabrera 1, Universidad Autónoma de MadridAbstract Tubular aggregates (TA) are honeycomb-like arrays of sarcoplasmic-reticulum (SR) tubules affecting aged glycolytic fibers of male individuals and inducing severe sarcomere disorganization and muscular pain. TA develop in skeletal muscle from Tubular Aggregate Myopathy (TAM) patients as well as in other disorders including endocrine syndromes, diabetes, and ageing, being their primary cause unknown. Nowadays, there is no cure for TA. Intriguingly, both hypoxia and calcium dyshomeostasis prompt TA formation, pointing to a possible role for mitochondria in their setting. However, a functional link between mitochondrial dysfunctions and TA remains unknown. Herein, we investigate the alteration in muscle-proteome of TAM patients, the molecular mechanism of TA onset and a potential therapy in a preclinical mouse model of the disease. We show that in vivo chronic inhibition of the mitochondrial ATP synthase in muscle causes TA. Upon long-term restrained oxidative phosphorylation (OXPHOS), oxidative soleus experiments a metabolic and structural switch towards glycolytic fibers, increases mitochondrial fission, and activates mitophagy to recycle damaged mitochondria. TA result from the overresponse of the fission controller DRP1, that upregulates the Store-Operate-Calcium-Entry and increases the mitochondria-SR interaction in a futile attempt to buffer calcium overloads upon prolonged OXPHOS inhibition. Accordingly, hypoxic muscles cultured ex vivo show an increase in mitochondria/SR contact sites and autophagic/mitophagic zones, where TA clusters grow around defective mitochondria. Moreover, hypoxia triggered a stronger TA formation upon ATP synthase inhibition, and this effect was reduced by the DRP1 inhibitor mDIVI. Remarkably, the muscle proteome of TAM patients displays similar alterations in mitochondrial dynamics and in ATP synthase contents. In vivo edaravone treatment in mice with restrained OXPHOS restored a healthy phenotype by prompting mitogenesis and mitochondrial fusion. Altogether, our data provide a functional link between the ATP synthase/DRP1 axis and the setting of TA, and repurpose edaravone as a possible treatment for TA-associated disorders.https://doi.org/10.1038/s41419-022-05016-z |
| spellingShingle | Cristina Sánchez-González Juan Cruz Herrero Martín Beñat Salegi Ansa Cristina Núñez de Arenas Brina Stančič Marta P. Pereira Laura Contreras José M. Cuezva Laura Formentini Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates Cell Death and Disease |
| title | Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates |
| title_full | Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates |
| title_fullStr | Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates |
| title_full_unstemmed | Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates |
| title_short | Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates |
| title_sort | chronic inhibition of the mitochondrial atp synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates |
| url | https://doi.org/10.1038/s41419-022-05016-z |
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