Mechanobiology June 26th - June 2nd 2016

Mechanobiology: June 26th  - June 2nd 2016

Cav1.1 controls frequency-dependent events regulating adult skeletal muscle plasticity
Gonzalo Jorquera, Francisco Altamirano, Ariel Contreras-Ferrat, Gonzalo Almarza, Sonja Buvinic, Vincent Jacquemond, Enrique Jaimovich, Mariana Casas


An important pending question in neuromuscular biology is how skeletal muscle cells decipher the stimulation pattern coming from motoneurons to define their phenotype as slow or fast twitch muscle fibers. We have previously shown that voltage-gated L-type calcium channel (Cav1.1) acts as a voltage sensor for activation of inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3]-dependent Ca2+ signals that regulates gene expression. ATP released by muscle cells after electrical stimulation through pannexin-1 channels plays a key role in this process. We show now that stimulation frequency determines both ATP release and Ins(1,4,5)P3 production in adult skeletal muscle and that Cav1.1 and pannexin-1 colocalize in the transverse tubules. Both ATP release and increased Ins(1,4,5)P3 was seen in flexor digitorum brevis fibers stimulated with 270 pulses at 20 Hz, but not at 90 Hz. 20 Hz stimulation induced transcriptional changes related to fast-to-slow muscle fiber phenotype transition that required ATP release. Addition of 30 µM ATP to fibers induced the same transcriptional changes observed after 20 Hz stimulation. Myotubes lacking the Cav1.1-α1 subunit released almost no ATP after electrical stimulation, showing that Cav1.1 has a central role in this process. In adult muscle fibers, ATP release and the transcriptional changes produced by 20 Hz stimulation were blocked by both the Cav1.1 antagonist nifedipine (25 µM) and by the Cav1.1 agonist (-)S-BayK 8644 (10 µM). We propose a new role for Cav1.1, independent of its calcium channel activity, in the activation of signaling pathways allowing muscle fibers to decipher the frequency of electrical stimulation and to activate specific transcriptional programs that define their phenotype.


  • Author contributions

    M.C., E.J., S.B. and V.J. designed methods and experiments; G.J., F.A., A.C.F., G.A., V.J. and M.C. performed the experiments; G.J., M.C., A.C.F., S.B. and V.J. analyzed the data; M.C., G.J., S.B., E.J., V.J. interpreted the results; and M.C. wrote the paper.

  • Funding

    This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico [grant numbers 1110467 to E.J., M.C. and S.B.-11100454 to S.B., 3110170 to A.C.F.]; Comisión Nacional de Investigación Científica y Tecnológica [grants ACT-1111 to E.J., M.C. and S.B., AT 24110054 to G.J., AT 24100066 to F.A., 79090021 to S.B.]; Programa de Cooperación Científica Internacional Comisión Nacional de Investigación Científica y Tecnológica – Centre National de la Recherche Scientifique (CONICYT-CNRS EDC24748) to E.J., V.J. and M.C.; Program U-INICIA VID 2011, grant UINICIA 02/12M, and the University of Chile to M.C.

  • Supplementary material available online at

  • Accepted December 11, 2012.
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