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Role of Fam134b-driven endoplasmic reticulum (ER)-phagy in sarcopenia

Research Project
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01.01.2023
 - 31.12.2023

Autophagy is a process by which cells remove damaged organelles or protein aggregates to maintain cellular homeostasis. ER-phagy is a recently identified form of autophagy, which clears damaged parts of ER membrane. To elicit ER-phagy, specific ER-bound proteins recognize ER damage and recruit autophagy machinery. The ER is particularly interesting in myofibers because it adopts a unique structure of a very thin sheet attached underneath the plasma membrane. Proper ion flux through muscle ER is essential for contraction. Also, ER is an integral component of anchoring myonuclei at the cell periphery. Despite the obvious importance of the ER in myofibers, it is unknown how the quality of the ER is controlled and whether it is affected during ageing. From snRNA-Seq studies, a novel nuclear population was identified in aged muscles that included Fam134b as a distinguishing marker gene. Our consortium independently confirmed that Fam134b transcripts are increased during muscle ageing in bulk RNA-seq (Börsch et al., 2021; Fig. 1B) and snRNA-FISH (Fig. 1C). We hypothesize that increased Fam134b expression drives ER-phagy during muscle ageing and, importantly, that manipulation of ER-phagy can mitigate sarcopenia. To begin to tackle this question, we have joined forces between two groups with expertise on myonuclear gene expression (Kim) and muscle ageing and mTORC1 signaling (Rüegg), respectively. With the support of Eucor_seed, we aim to obtain foundational data to strengthen our hypothesis and secure larger future funding. Specifically, we will 1) test our core idea that ER-phagy flux is altered in aged muscles and examine its relationship to the mTORC1 pathway, 2) investigate how modulating Fam134b expression affects muscle performance in young and old mice, and 3) take the first step in identifying upstream regulators of Fam134b expression during ageing.

Funding

Role of Fam134b-driven endoplasmic reticulum (ER)-phagy in sarcopenia

Weitere Europäische Forschungsprojekte (Eurostars, ESF, Interreg etc.) (GrantsTool), 01.2023-12.2023 (12)
PI : Rüegg, Markus A..

Members (1)

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Markus A. Rüegg

Principal Investigator