title: Ca(2+) permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca(2+) signaling to sustain muscle function.
abstract: BACKGROUND
  Ca(2+) influx through CaV1.1 is not required for skeletal muscle excitation-contraction coupling, but whether Ca(2+) permeation through CaV1.1 during sustained muscle activity plays a functional role in mammalian skeletal muscle has not been assessed.
  
  
  METHODS
  We generated a mouse with a Ca(2+) binding and/or permeation defect in the voltage-dependent Ca(2+) channel, CaV1.1, and used Ca(2+) imaging, western blotting, immunohistochemistry, proximity ligation assays, SUnSET analysis of protein synthesis, and Ca(2+) imaging techniques to define pathways modulated by Ca(2+) binding and/or permeation of CaV1.1. We also assessed fiber type distributions, cross-sectional area, and force frequency and fatigue in isolated muscles.
  
  
  RESULTS
  Using mice with a pore mutation in CaV1.1 required for Ca(2+) binding and/or permeation (E1014K, EK), we demonstrate that CaV1.1 opening is coupled to CaMKII activation and refilling of sarcoplasmic reticulum Ca(2+) stores during sustained activity. Decreases in these Ca(2+)-dependent enzyme activities alter downstream signaling pathways (Ras/Erk/mTORC1) that lead to decreased muscle protein synthesis. The physiological consequences of the permeation and/or Ca(2+) binding defect in CaV1.1 are increased fatigue, decreased fiber size, and increased Type IIb fibers.
  
  
  CONCLUSIONS
  While not essential for excitation-contraction coupling, Ca(2+) binding and/or permeation via the CaV1.1 pore plays an important modulatory role in muscle performance.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Chang Seok
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Adan
authors.initials: A
authors.lastname: Dagnino-Acosta
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642 USA.
authors.forename: Viktor
authors.initials: V
authors.lastname: Yarotskyy
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Hanna
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642 USA.
authors.forename: Alla
authors.initials: A
authors.lastname: Lyfenko
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Knoblauch
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Dimitra K
authors.initials: DK
authors.lastname: Georgiou
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Poché
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Swank
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Long
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Iskander I
authors.initials: II
authors.lastname: Ismailov
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Lanner
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Tran
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: KeKe
authors.initials: K
authors.lastname: Dong
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Rodney
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Dickinson
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Pumin
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642 USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Hamilton
keywords: CaM kinase II; CaV1.1; Fatigue; Fiber type; Protein synthesis and Skeletal muscle