Research ArticleSarcopenia

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

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Science Translational Medicine  06 Nov 2019:
Vol. 11, Issue 517, eaaw1131
DOI: 10.1126/scitranslmed.aaw1131

Counteracting aging muscles

The mechanisms mediating age-related muscle atrophy are not completely understood. Now, Traoré et al. used mouse models to elucidate the mechanisms mediating age-related muscle atrophy. The authors first showed that muscle denervation triggered compensatory mechanisms to counteract excessive muscle loss; after denervation, muscle cells increased the expression of an embryonic isoform of the voltage-gated calcium channel (CaVβ1E) to limit muscle loss. The expression of CaVβ1E was reduced in aged muscles in mice. Moreover, CaVβ1E expression in skeletal muscles correlated with muscle mass in a cohort of aged individuals. The results suggest that targeting CaVβ1E could contribute to prevent muscle atrophy associated with aging and disuse.


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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