As people live longer, we are facing a rapid rise in the number of older adults living with muscle weakness and loss of muscle mass, a condition known as sarcopenia. Sarcopenia increases the risk of falls and fractures, loss of independence, hospitalisation and long‑term care, with substantial costs for healthcare systems and families and a heavy impact on elderly people's quality of life. Current sarcopenia management relies on exercise and lifestyle counselling, two extremely important but often insufficient strategies to counteract the worsening of muscle weakness. There is therefore a strong need for new, targeted therapies that can help maintain muscle strength and function in later life.
Recent research suggests that sarcopenia is not only a “muscle-related disease”, but also has a major nerve component. With ageing, some motor nerves that control muscle fibres degenerate, and the specialised connections between nerves and muscles, called neuromuscular junctions, become damaged. In healthy individuals, many of these connections can be repaired, but in older people the restoration of neuromuscular junctions is often incomplete, leading to long‑term muscle weakness. Preserving these nerve–muscle connections, or restoring them when they fail, is emerging as a promising strategy to slow down sarcopenia progression.
My project focuses on a signalling pathway centred on prostaglandin E2 (PGE2) and the enzyme 15‑prostaglandin dehydrogenase (15‑PGDH), which degrades PGE2. Previous work from my host laboratory showed that 15‑PGDH levels increase with age, lowering pro-regenerative PGE2 signalling and contributing to muscle wasting. Inhibiting 15‑PGDH with a small molecule can restore PGE2 to youthful levels and improve muscle strength in aged mice. Building on these findings, my fellowship investigates whether the 15‑PGDH/PGE2 pathway is a key driver of nerve–muscle disconnection in ageing, and whether its modulation could be developed into a treatment for sarcopenia and related neuromuscular conditions.
In my project, I aim to show whether muscle denervation (loss of nerve input) in mice triggers an increase in 15‑PGDH in muscle and to test whether its inhibition protects motor neurons and neuromuscular junctions in injured and aged mice, representing a viable therapeutic strategy. I further aim to translate these findings to humans by assessing whether an imbalance in the 15‑PGDH/PGE2 pathway is also present in sarcopenic patients. To achieve this, I will obtain in-vivo data and muscle biopsies from young, healthy aged and sarcopenic individuals. I will generate multi-omics data (single nuclei RNA-sequencing and spatial proteomics) to molecularly characterize young, aged and sarcopenic muscles and link this molecular signature, including 15-PGDH/PGE2 signalling axis, to their in-vivo morpho-functional features.
By linking basic mechanisms in mice to human data, and by generating large, openly shareable datasets, the project is expected to contribute to the development of new therapeutic strategies for sarcopenia. If successful, this work could support future clinical trials of 15 PGDH inhibitors or related compounds, help identify individuals at higher risk of rapid muscle decline, and ultimately contribute to healthier ageing, reduced disability and lower healthcare costs in ageing societies.
