Project description
Restoring muscle strength to combat ageing
As we age, muscle mass and strength gradually decline, sometimes leading to sarcopenia. This is a condition that increases the risk of falls, fractures, and loss of independence. Key drivers of sarcopenia include the breakdown of neuromuscular junctions (NMJs), the vital connections between nerves and muscles. With this in mind, the EU-funded RestorAGING project explores how prostaglandin E2 (PGE2), a molecule that stimulates tissue regeneration, affects NMJ integrity. In aged muscles, PGE2 levels drop due to increased activity of its degrading enzyme, 15-PGDH. By studying mice and human muscle samples, RestorAGING will investigate whether restoring PGE2 can repair NMJs and improve muscle function. This will lead to a therapeutic approach to slow or reverse sarcopenia.
Objective
Aging is characterised by a progressive decline in muscle mass and force, potentially resulting in the insurgence of sarcopenia. Sarcopenic patients are at an increased risk of falls and fractures, with a concordant decrease in mobility and personal independence. Evidence suggests that key determinants of sarcopenia insurgence are muscle denervation, failure of its reinnervation and degeneration of neuromuscular junctions (NMJ), representing the connection between the nerve and the muscle and essential for muscle function. This MSCA project will inform our understanding on the interplay between prostaglandin signalling and the NMJ in the onset and treatment of sarcopenia. Prostaglandin E2 (PGE2) stimulates tissue regeneration. Its levels are reduced in aged human and mice skeletal muscles due to increased activity of its degrading enzyme 15- prostaglandin dehydrogenase (15-PGDH). Inhibition of 15-PGDH in aged rodents restores PGE2 concentrations to youthful levels, increasing muscle mass, strength and endurance. However, the mechanisms underlying how 15-PGDH/PGE2 modulation exerts these effects are not well understood. Here, I will show how PGE2 impacts NMJ integrity in mice, establishing if restoration of its signalling restores NMJs innervation progressively lost in aging. My final aim is to determine whether boosting PGE2 levels via 15-PGDH inhibition represents a viable therapeutic strategy to treat sarcopenia. To confirm the relevance of the dysregulated 15-PGDH/PGE2 axis in determining NMJ alterations in humans, I will perform single nuclei RNASeq and spatial proteomics (CODEX) on muscle samples of young and aged healthy, pre-sarcopenic and sarcopenic individuals. I will integrate the molecular data with in-vivo muscle morphology and function, (1) to reveal whether 15-PGDH expression, activity and localization is different in sarcopenic muscle and correlates with any in-vivo parameter and (2) to generate a macro-to-micro atlas of human aging and sarcopenia.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-GF - HORIZON TMA MSCA Postdoctoral Fellowships - Global Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2022-PF-01
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35122 Padova
Italy
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