Exercise promotes muscle growth, whereas inactivity leads to muscle atrophy, a process that can be opposed by direct electrical stimulation. Noting that L-type Ca2+ channels have been implicated in activity-dependent changes in neuronal transcription, Piétri-Rouxel et al. explored the role of the α1S subunit of the muscle L-type Ca2+ channel [known as the dihydropyridine receptor (DHPR)] in linking muscle activity to muscle growth. Intramuscular injection of U7 snRNA chimeras designed to disrupt α1S pre-mRNA splicing (so as to skip exon 16 and thereby shift the mRNA reading frame) elicited a substantial decrease in unskipped α1S mRNA in mouse tibialis anterior muscle by 2 months after injection. A decrease in α1S protein was apparent 6 months after injection, as well as substantial loss of muscle mass, resulting from a decrease in fiber diameter, and increased fibrosis. Further analysis revealed that α1S knockdown led to a decrease in neuronal nitric oxide synthase (nNOS) abundance, accompanied by redistribution of nNOS from the sarcolemma to the cytoplasm, and translocation of the transcription factor FoxO3A to the nucleus (changes consistent with muscle atrophy secondary to inactivity). The α1S knockdown also led to increased abundance of the mRNA encoding genes associated with autophagy and elicited the appearance of autophagosomes. Muscle α1S functions as a Ca2+ channel along the transverse (T) tubules and as a voltage sensor for excitation-contraction coupling at the triad, with a minor fraction localized to the sarcolemma. The authors confirmed this distribution by three-dimensional confocal analysis of control flexor digitorum brevis muscle; intriguingly, however, α1S knockdown was specifically associated with loss of this minor sarcolemmal fraction. The authors thus propose that this sarcolemmal fraction of α1S may act as a sensor to couple muscle activity with its anabolic or catabolic state.
F. Piétri-Rouxel, C. Gentil, S. Vassilopoulos, D. Baas, E. Mouisel, A. Ferry, A. Vignaud, C. Hourdé, I. Marty, L. Schaeffer, T. Voit, L. Garcia, DHPR α1S subunit controls skeletal muscle mass and morphogenesis. EMBO J. 29, 643–654 (2010). [PubMed]