External seminar: Sestina FALCONE
Simona SACCANI invites: Sesistna FALCONE – Sorbonne Université UMRS974-Inserm-Institut de Myologie
« Identification of CaVβ1 subunits and their role in the neuromuscular system from embryo to aging«
Abstract: Voltage-gated Ca2+ channels (VGCCs) are regulated by four CaVβ subunits (CaVβ1-CaVβ4), each showing specific expression patterns in excitable cells. While primarily known for regulating VGCC function, CaVβ proteins also have channel-independent roles, including the modulation of gene expression. Among these, CaVβ1 is expressed in skeletal muscle as multiple isoforms. We investigated the lesser-known embryonic/perinatal CaVβ1 isoforms and their roles in neuromuscular junction (NMJ) formation, maturation, and maintenance. We found that CaVβ1 isoform expression is developmentally regulated through differential promoter activation. Specifically, CaVβ1A is expressed in embryonic muscle and reactivated in denervated adult muscle, alongside the known CaVβ1E isoform. Nerve injury in adult muscle triggers a shift in promoter usage, resulting in re-expression of embryonic/perinatal Cacnb1A and Cacnb1E transcripts. Morphological analyses demonstrates that these isoforms contribute to NMJ formation. Additionally, their expression during post-natal development is essential for NMJ maturation and long-term maintenance.
Of note, our work demonstrates that aged mouse muscle expresses lower quantity of embryonic CaVβ1s compared with young muscle, displaying an altered response to denervation. Conversely, CaVβ1E overexpression improves mass wasting in aging muscle in mice. We have also identified the human CaVβ1E analogous and shown a correlation between CaVβ1E expression in human muscles and age-related muscle mass decline. These findings reveal previously unrecognized roles of CaVβ1 isoforms beyond VGCC regulation, highlighting their significance in neuromuscular system development and homeostasis