Deciphering the pathophysiological role and regulation of denervation-induced sub-synaptic remodelling in skeletal muscle
Description: Skeletal muscle deterioration with age, known as sarcopenia, has become a major global public health issue, with profound clinical, social, and economic implications. A hallmark of sarcopenia is the progressive loss of muscle innervation, which contributes to muscle decline. Yet, the underlying pathomechanisms remain largely unknown. The neuromuscular junction (NMJ), which allows the transmission of neural information to skeletal muscle, defines a highly specialized region (i.e., sub-synaptic or endplate) within muscle fibres. Its integrity and functioning hinge on the accumulation of synaptic proteins specifically at the endplate, which relies on the maintenance of distinct genetic programs in sub- and non-synaptic myonuclei within the same fibre. Loss of functional innervation triggers synaptic remodelling and genetic reprogramming along muscle fibres, which determine their ability to adapt and potentially recover. Our understanding of the integrated program governing the coordinated response of sub- and non-synaptic regions in muscle fibres remains fragmented. In particular, the molecular changes primarily induced by nerve injury, which drive the broader muscle response, remain elusive. The mechanisms underlying sub-synaptic nuclear reprogramming and their role in preserving endplate integrity are also unknown.The overall goal of our project is to characterize the sub-synaptic processes locally triggered by denervation, and determine their significance in the integrated response of muscle fibres and their recovery capacity. Building on single nuclei RNA sequencing data obtained in the lab, we will analyse the role of sub-synaptic factors and processes in endplate maintenance after denervation and in the reinnervation capacity of skeletal muscle. To this end, we have validated cutting-edge tools to track spatiotemporal transcriptional changes along muscle fibres and to modulate candidate genes in the sub-synaptic region. Our research program is structured in three synergistic axes: AXIS 1 investigates the physiological role of sub-synaptic changes in the integrated muscle response to denervation. Specifically, we will examine 1) the spatiotemporal distribution of nuclear reprogramming along fibres, 2) the impact of synaptic gene expression changes in sub-synaptic nuclei on endplate plasticity, and 3) the role of specific transcription factors in sub-synaptic reprogramming after denervation. AXIS 2 evaluates the importance of Ca2+ fluxes at the endplate in its maintenance and plasticity. Based on our recent results on Store-Operated Calcium Entry (SOCE), we will explore the function of regulators and downstream effectors of SOCE at the endplate, and characterize the role of other sub-synaptic Ca2+ fluxes after nerve injury.AXIS 3 examines the consequences of sub-synaptic deregulations of mTORC1 and Ca2+ fluxes on endplate integrity and muscle reinnervation capacity. Their implication in NMJ alterations and the decline of muscle plasticity, with a focus on sarcopenia, will be considered in both mice and humans.Building on our recent discoveries and leveraging state-of-the-art methodologies, our project will identify molecular mechanisms governing endplate maintenance and plasticity in skeletal muscle. Unravelling these processes is essential to understand NMJ decline in pathological conditions and will enhance our ability to anticipate and mitigate skeletal muscle deterioration, with potent clinical and social benefits.
Amount: CHF 611,100
Funding type: research
Funder scheme: Project funding
Start date: 2025-12-01
End date: 2029-11-30
Investigator: Castets, Perrine
Institution: University of Geneva – GE
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 0
Funder award ID: 10006151
OpenAlex ID: G8758994747