title: Progressive impairment of CaV1.1 function in the skeletal muscle of mice expressing a mutant type 1 Cu/Zn superoxide dismutase (G93A) linked to amyotrophic lateral sclerosis.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that is typically fatal within 3-5 years of diagnosis. While motoneuron death is the defining characteristic of ALS, the events that underlie its pathology are not restricted to the nervous system. In this regard, ALS muscle atrophies and weakens significantly before presentation of neurological symptoms. Since the skeletal muscle L-type Ca(2+) channel (CaV1.1) is a key regulator of both mass and force, we investigated whether CaV1.1 function is impaired in the muscle of two distinct mouse models carrying an ALS-linked mutation.
  
  
  METHODS
  We recorded L-type currents, charge movements, and myoplasmic Ca(2+) transients from dissociated flexor digitorum brevis (FDB) fibers to assess CaV1.1 function in two mouse models expressing a type 1 Cu/Zn superoxide dismutase mutant (SOD1(G93A)).
  
  
  RESULTS
  In FDB fibers obtained from "symptomatic" global SOD1(G93A) mice, we observed a substantial reduction of SR Ca(2+) release in response to depolarization relative to fibers harvested from age-matched control mice. L-type current and charge movement were both reduced by ~40 % in symptomatic SOD1(G93A) fibers when compared to control fibers. Ca(2+) transients were not significantly reduced in similar experiments performed with FDB fibers obtained from "early-symptomatic" SOD1(G93A) mice, but L-type current and charge movement were decreased (~30 and ~20 %, respectively). Reductions in SR Ca(2+) release (~35 %), L-type current (~20 %), and charge movement (~15 %) were also observed in fibers obtained from another model where SOD1(G93A) expression was restricted to skeletal muscle.
  
  
  CONCLUSIONS
  We report reductions in EC coupling, L-type current density, and charge movement in FDB fibers obtained from symptomatic global SOD1(G93A) mice. Experiments performed with FDB fibers obtained from early-symptomatic SOD1(G93A) and skeletal muscle autonomous MLC/SOD1(G93A) mice support the idea that events occurring locally in the skeletal muscle contribute to the impairment of CaV1.1 function in ALS muscle independently of innervation status.
authors.affiliation: Department of Medicine-Cardiology Division, University of Colorado School of Medicine, 12700 East 19th Avenue, B-139, Aurora, CO 80045 USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Beqollari
authors.affiliation: Department of Medicine-Cardiology Division, University of Colorado School of Medicine, 12700 East 19th Avenue, B-139, Aurora, CO 80045 USA.
authors.forename: Christin F
authors.initials: CF
authors.lastname: Romberg
authors.affiliation: Institute Pasteur Cenci-Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, La Sapienza University, Via A. Scarpa, 14, 00161 Rome, Italy ; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Dobrowolny
authors.affiliation: Institute Pasteur Cenci-Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, La Sapienza University, Via A. Scarpa, 14, 00161 Rome, Italy ; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Martini
authors.affiliation: Department of Biological Sciences, College of Science and Mathematics, Wright State University, 235A Biological Sciences, 3640 Colonel Glenn Highway, Dayton, OH 45435 USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Voss
authors.affiliation: Institute Pasteur Cenci-Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, La Sapienza University, Via A. Scarpa, 14, 00161 Rome, Italy ; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Musarò
authors.affiliation: Department of Medicine-Cardiology Division, University of Colorado School of Medicine, 12700 East 19th Avenue, B-139, Aurora, CO 80045 USA.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Bannister
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling; D056966:Excitation Contraction Coupling; D020022:Genetic Predisposition to Disease; D008297:Male; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000201:enzymology; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000294:innervation / Q000503:physiopathology; D009154:Mutation; D010641:Phenotype; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: C529218:CACNA1S protein, mouse; D020746:Calcium Channels, L-Type; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: ALS; Amyotrophic lateral sclerosis; CaV1.1; Excitation-contraction coupling; L-type; Neuromuscular disease; SOD1; Skeletal muscle