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Sci Transl Med. 2019 Nov 6;11(517). pii: eaaw1131. doi: 10.1126/scitranslmed.aaw1131.

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

Author information

1
Inovarion, F-75013, Paris France.
2
Sorbonne Université, Centre de Recherche en Myologie, UM76, INSERM U974, Institut de Myologie, F-75013, Paris, France.
3
Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
4
GenoSplice, F-75005 Paris, France.
5
Sorbonne Université, INSERM, UMS28, F-75013 Paris, France.
6
Sorbonne Université, Centre de Recherche en Myologie, UM76, INSERM U974, Institut de Myologie, F-75013, Paris, France. sestinaf@gmail.com france.pietri-rouxel@upmc.fr.

Abstract

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 β subunit (CaVβ1) 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 CaVβ1E. CaVβ1E 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 CaVβ1E compared with young muscle, displaying an altered GDF5-dependent response to denervation. Conversely, CaVβ1E overexpression improved mass wasting in aging muscle in mice by increasing GDF5 expression. We also identified the human CaVβ1E analogous and show a correlation between CaVβ1E expression in human muscles and age-related muscle mass decline. These results suggest that strategies targeting CaVβ1E or GDF5 might be effective in reducing muscle mass loss in aging.

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