Skeletal muscle is a complex tissue which requires a correct balance of myotrophic factors and a functional innervation with normal excitation contraction (EC) coupling and muscle activity to maintain mass and function. L-type Ca2+ channels are made of five subunits (α1S, α2, β, γ, δ). The α1S, known as the dihydropyridine receptor (DHPR), is a four-repeat transmembrane protein which has a dual function in skeletal muscle: it forms the L-type Ca2+ channel in T-tubules and is the voltage sensor of EC coupling at the level of triads. It has been proposed that L-type Ca2+ channels might also be voltage-gated sensors linked to transcriptional activity controlling differentiation. We hypothesize here that subtle modification of α1S contents in adult muscle could allow to decipher unexpected functions for this multi-functional protein. By using the U7-exon skipping strategy, we have combined optimized U7snRNA and gene transfer to achieve long-lasting down regulation of α1S in adult skeletal muscle. Treated muscles underwent massive atrophy while still displaying significant amounts of α1S in the tubular system and being not paralyzed. This atrophy implicated the autophagy-pathway which was triggered by nNOS redistribution, activation of FoxO3A, up-regulation of autophagy-related genes and autophagosome formation. Subcellular investigations showed that this atrophy was correlated with the disappearance of a fraction of α1S located throughout the sarcolemma. Our results reveal for the first time that this sarcolemmal fraction could play a role in a signaling pathway determining muscle anabolic or catabolic state and might act as a molecular sensor of muscle activity.