«Decoding the gene networks that control proteostasis during muscle wasting for developing a RNA-based therapeutic approach»

02.04.2026 12:30 – 13:30

Maintaining the integrity of organelles and proteins despite the cellular stresses that arise from environmental pressure is essential for life. The time-dependent accumulation of cellular damage is widely considered to be the general cause of cellular degeneration and disease onset. Alteration of the protein quality control, called the loss of proteostasis, contributes to impairment of macromolecule and organelle function and is considered among the primary hallmark of aging, morbidity and mortality. Postmitotic tissues such as brain and striated muscles are particularly vulnerable to changes of proteostasis. Marco Sandri and his group have shown that the regulation of protein and organelles turnover is under the control of transcription factors belonging to different signalling pathways.

In the first part, Pr Sandri will describe why physical activity and exercise are beneficial for human health, while sedentary life and inactivity are one of the major detrimental behaviours of industrialized societies that contribute to mortality and morbidity. He has shown that these lifestyles impact on mitochondrial function, bioenergetics and glucose metabolism in skeletal muscles. He will discuss how the shape of mitochondrial network during inactivity regulates signalling pathways that alter mitophagy and promote a secretory pattern to induce tissue senescence and organism premature ageing. He will show how his group screened and identified a novel autophagy regulator gene that is required for a healthy ageing.

In the second part he will particularly focus on the mechanisms that link mitochondrial dysfunction to cancer-induced cachexia, a metabolic syndrome responsible of 30% cancer death. By combining single nucleus (sn) multiomic approach, spatial transcriptomic and human derived neuromuscular organoids (NMOs), Pr Sandri and his group have characterized the cellular and gene networks underpinning cachexia during cancer growth. By integrating the snRNAseq with ATACseq data sets, they identified the transcription factors that are recruited by cancer growth in the different cell types of muscle tissues.

Pr Sandri's findings depicted an unexpected scenario in which almost all the cell types activated a similar catabolic signature and synergised to promote a pro-catabolic anti-neurotrophic environment. By having decoded which transcription factors are recruited, he then developed an RNA-based therapeutic approach to block the most relevant ones. By targeting FoxO1 and FoxO3 transcription factors and the ubiquitin ligase, TRIM63, his group reverted the catabolic signature in murine models of cancer cachexia as well as in patients' derived neuromuscular organoids. These findings pave the way for an innovative RNA multi-target therapy that matches with the concept of precision medicine.

Lieu

Bâtiment: CMU

Auditoire Müller

entrée libre

Fichiers joints

afficheA3_FIB_Sandri.pdf

176 Kb