Deciphering the mechanisms governing skeletal muscle plasticity is essential for understanding pathophysiological processes, including age-related sarcopenia. Muscle activity reverses atrophy, but the connection between these processes is unknown. The voltage sensor CaV1.1 has a central role in excitation contraction coupling, raising the possibility that it may also initiate the adaptive response to changes in muscle activity. Here, we reveal the existence of a transcription switch for the beta subunit of CaV1.1 (CaVβ1) that depends on the innervation state of the muscle. We show that denervation triggers the reexpression of a novel embryonic isoform, CaVβ1E. CaVβ1E boosts downstream GDF5 signaling to counteract muscle loss after denervation. We further report that aged muscle expresses significantly reduced levels of CaVβ1E and that CaVβ1E overexpression in aging muscle reduces sarcopenia by rescuing GDF5 expression. Crucially, we also identify human hCaVβ1E and show a tight negative correlation between hCaVβ1E expression and age-related sarcopenia in people, suggesting that the mechanisms underlying muscle mass homeostasis are conserved across species