An embryonic CaVβ1 isoform promotes muscle mass maintenance via GDF5 signaling in adult mouse

Massiré Traoré (1) , Christel Gentil (1) , Chiara Benedetto (1) , Jean-Yves Hogrel (2) , Pierre de La Grange (3) , Bruno Cadot (1) , Sofia Benkhelifa-Ziyyat (1) , Laura Julien (1) , Mégane Lemaitre (4) , Arnaud Ferry (1) , France Pietri-Rouxel (1) , Sestina Falcone (1)

1 Centre de recherche en Myologie – U974 SU-INSERM
2 Institut de Myologie
3 GenoSplice [Paris]
4 UMS28 - Phénotypage du petit animal

Deciphering the mechanisms that govern skeletal muscle plasticity is essential to understand its pathophysiological processes, including age-related sarcopenia. The voltage-gated calcium channel CaV1.1 has a central role in excitation-contraction coupling (ECC), raising the possibility that it may also initiate the adaptive response to changes during muscle activity. Here, we revealed the existence of a gene transcription switch of the CaV1.1  subunit (CaV1) that is dependent on the innervation state of the muscle in mice. In a mouse model of sciatic denervation, we showed increased expression of an embryonic isoform of the subunit that we called CaV1E. CaV1E boosts downstream growth differentiation factor 5 (GDF5) signaling to counteract muscle loss after denervation in mice. We further reported that aged mouse muscle expressed lower quantity of CaV1E compared with young muscle, displaying an altered GDF5-dependent response to denervation. Conversely, CaV1E overexpression improved mass wasting in aging muscle in mice by increasing GDF5 expression. We also identified the human CaV1E analogous and show a correlation between CaV1E expression in human muscles and age-related muscle mass decline. These results suggest that strategies targeting CaV1E or GDF5 might be effective in reducing muscle mass loss in aging.

Domaines: Organisation et fonctions cellulaires [q-bio.SC]; Physiologie [q-bio.TO]

Massiré Traoré, Christel Gentil, Chiara Benedetto, Jean-Yves Hogrel, Pierre de La Grange, et al.. An embryonic CaVβ1 isoform promotes muscle mass maintenance via GDF5 signaling in adult mouse. Science Translational Medicine, 2019, 11 (517), ⟨10.1126/scitranslmed.aaw1131⟩. ⟨hal-02382706⟩