CE45 - Mathématique, informatique, automatique, traitement du signal pour répondre aux défis de la biologie et de la santé

Systematic functional analysis of mitochondrial dynamics in healthy young, aged and sarcopenic muscle – MITO-DYNAMICS

MITO-DYNAMICS

In the MITO-DYNAMICS project, we aim to identify mitochondrial processes and their regulators responsible for muscle wasting (sarcopenia) during ageing and in disease conditions. <br />We proposed a systematic and quantitative approach to understand the molecular, morphological and physiological dynamics of mitochondria comparing young, old and sarcopenic muscles of mice and flies. This will be complemented by the development of an integrative analysis platform, mitoXplorer.

Systematic functional analysis of mitochondrial dynamics in healthy young, aged and sarcopenic muscle

In the MITO-DYNAMICS project, we aim to identify mitochondrial processes and their regulators that are responsible for muscle wasting (sarcopenia) during ageing and in disease conditions. Currently, we lack a coherent quantitative understanding of the contribution from mitochondrial dysfunction to sarcopenia during ageing or disease. We also know little about the molecular changes within mitochondria during ageing or disease-associated sarcopenia. Understanding these molecular changes will be essential to develop therapies preventing age- or disease-induced muscle loss. Therefore, we propose a systematic and quantitative approach to understand the molecular, morphological and physiological dynamics of mitochondria comparing young, old and sarcopenic muscles of mice and flies.<br /><br />Using a tailored, highly sophisticated strategy and tool-set for computational data analysis and integration of mitochondrial expression and functional dynamics (Aim 1), we propose to investigate the following central biological questions:<br />1) How does the lack of muscle activity during ageing impact mitochondrial gene expression, mitochondrial structure and mitochondrial function in a Drosophila adult muscle model (Aim 2)?<br />2) Which conserved genes lead to age- or pancreatic cancer-induced sarcopenia in mouse skeletal muscle (Aim 3)?<br />3) Which are the molecular mechanisms of sedentary behavior-induced or sarcopenia-induced regulators of mitochondrial functions (Aim 4)?

With the mitoXplorer platform, we will analyse and integrate transcriptomic, proteomic, metabolic and morphological data of muscle mitochondria from mouse and flies during ageing and in sarcopenia.
Leg muscle from mice between age 3m to 24m, as well as sarcopenic mice with pancreatic tumors will be analysed using 3P-MRI, transcriptomics, proteomics, mitochondrial functional measurements (w the SeaHorse instrument), as well as morphologically. At the same time, ageing flies in different exercise regimes (fly domes) will be analyzed using transcriptomics, proteomics, mitochondrial metabolic measurements and morphological studies. Using a dedicated, web-based analysis platform for mitochondrial expression dynamics, mitoXplorer, we will analyse and integrate these data between the two different species and identify key regulators of mitochondria during muscle ageing.

1. We have published the mitoXplorer 1.0 web-server (http://mitoxplorer.ibdm.univ-mrs.fr, Yim et al., NAR 2020)
2. We have integrated the AnnoMiner transcription factor enrichment tool with mitoXplorer to identify key mitochondrial transcriptional regulators (http://chimborazo.ibdm.univ-mrs.fr/AnnoMiner)
3. We have characterized in detail the structural and mechanical interplay between myofibrils and mitochondria in the flight muscle as well as in the leg muscle of Drosophila (Avellaneda, et al., BiorXiv 2020).
4. We have made available an automated mitochondrial segmentation software for light microscopy images based on deep learning for the Drosophila flight muscle (https://github.com/fabda/Myofibril_paper).
5.Software : mitoXplorer : mitoxplorer.ibdm.univ-mrs.fr
6. Software : AnnoMiner : chimborazo.ibdm.univ-mrs.fr/AnnoMiner
7. Software : mitochondrial segmentation tool : github.com/fabda/Myofibril_paper

In the MITO-DYNAMICS project, we aim to identify mitochondrial processes and their regulators responsible for muscle wasting (sarcopenia) during ageing and in disease conditions.
We proposed a systematic and quantitative approach to understand the molecular, morphological and physiological dynamics of mitochondria comparing young, old and sarcopenic muscles of mice and flies.
We are creating a systematic time-resolved resource of mitochondrial gene and protein expression dynamics, including mitochondrial metabolism and morphology in the ageing muscle of Drosophila and in sarcopenic mouse muscle. This is the first comprehensive, multi-facetted resource on muscle wasting, which has been collected under strictly controlled conditions.
Importantly, we are developing a highly versatile and user-friendly web-platform, mitoXplorer 2.0, for the in-depth analysis of mitochondrial gene expression dynamics, integrating mitochondrial function and morphology dynamics under different experimental conditions. This web-platform will allow to mine and visualize mitochondrial expression data, as well as facilitate exploration of potential regulatory pathways of mitochondrial dynamics. mitoXplorer 2.0 will be freely available to the research community.
With mitoXplorer 2.0 we expect to identify conserved key regulators of mitochondrial plasticity during ageing or disease. The identified molecular mechanisms of how these proteins modify mitochondrial function and physiology may result in strategies on how to treat muscle dysfunction in the ageing population or upon disease.

1. Yim A, et al., 2020, NAR 48(2) mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations. doi: 10.1093/nar/gkz1128
2. Jerome Avellaneda, Clement Rodier, Fabrice Daian, Thomas Rival, Nuno Miguel Luis, Frank Schnorrer. Myofibril and mitochondria morphogenesis are coordinated by a mechanical feedback mechanism in muscle. biorXiv 2020. doi: doi.org/10.1101/2020.07.18.209957.
3. Software : mitoXplorer : mitoxplorer.ibdm.univ-mrs.fr
4. Software : AnnoMiner : chimborazo.ibdm.univ-mrs.fr/AnnoMiner
5. Software : mitochondrial segmentation tool : github.com/fabda/Myofibril_paper

In the MITO-DYNAMICS project, we want to identify conserved key regulators of mitochondrial functions during age- and disease-associated muscle wasting (sarcopenia) by integrating system-wide, time-dependent mitochondrial expression, metabolic and morphological data across species. We will make use of two animal muscle model systems: mouse skeletal muscle of young and old, as well as cachexic pancreatic cancer mice; and the ageing Drosophila flight muscle of animals raised under three conditions of controlled exercise.
For data analysis and cross-species data integration, we will rely on a highly sophisticated analysis platform, which we have developed to monitor mitochondrial dynamics in different experimental conditions, tissues and model systems, the mitoXplorer platform (http://mitoxplorer.biochem.mpg.de). We will extend the mitoXplorer platform such that it will help us to identify conserved transcriptional regulators, as well as regulatory pathways of mitochondrial functions during sarcopenia.
We will moreover elucidate the molecular mechanism of selected, conserved key regulators in the Drosophila ageing flight muscle. We will make knock-out, as well as transgenic flies of selected gene candidates, test their flight performance, collect mitochondrial metabolic and morphological data during ageing and controlled exercise, look for interaction partners and, in case of transcription factors, identify potential direct target genes.
Resulting conserved key regulators of mitochondrial function during sarcopenia from the MITO-DYNAMICS project will open new avenues for targeted research of sarcopenia in the mouse model and might in the long run lead to novel therapeutic approaches to treat sarcopenia in the elderly and in cancer patients.

Project coordinator

Madame Bianca HABERMANN (Centre National de la Recherche Scientifique délégation Provence et Corse _Institut de Biologie du Développement de Marseille)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CNRS DR12_IBDM Centre National de la Recherche Scientifique délégation Provence et Corse _Institut de Biologie du Développement de Marseille
CRMBM Centre de résonance magnétique biologique et médicale
CRCM Dominique NOBILE

Help of the ANR 499,089 euros
Beginning and duration of the scientific project: January 2019 - 36 Months

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