title: Restricting calcium currents is required for correct fiber type specification in skeletal muscle.
abstract: Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact, alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Whether this is necessary for normal development and function of muscle is not known. However, splicing defects that cause aberrant expression of the calcium-conducting developmental CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here, we deleted CaV1.1 (Cacna1s) exon 29 in mice. These mice displayed normal overall motor performance, although grip force and voluntary running were reduced. Continued expression of the developmental CaV1.1e splice variant in adult mice caused increased calcium influx during EC coupling, altered calcium homeostasis, and spontaneous calcium sparklets in isolated muscle fibers. Contractile force was reduced and endurance enhanced. Key regulators of fiber type specification were dysregulated and the fiber type composition was shifted toward slower fibers. However, oxidative enzyme activity and mitochondrial content declined. These findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the secondary function of the calcium signal in the activity-dependent regulation of fiber type composition and to prevent muscle disease.
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Nasreen
authors.initials: N
authors.lastname: Sultana
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Dienes
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Ariane
authors.initials: A
authors.lastname: Benedetti
authors.affiliation: Department of Pharmacology, University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Petronel
authors.initials: P
authors.lastname: Tuluc
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Szentesi
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
authors.forename: Monika
authors.initials: M
authors.lastname: Sztretye
authors.affiliation: Division of Molecular Pathophysiology, Biocenter, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Rainer
authors.affiliation: Division of Histology and Embryology, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hess
authors.affiliation: Department of Pharmacology, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schwarzer
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Obermair
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Csernoch
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck 6020, Austria Bernhard.E.Flucher@i-med.ac.at.
authors.forename: Bernhard E
authors.identifier: 0000-0002-5255-4705
authors.initials: BE
authors.lastname: Flucher
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics*; D056966:Excitation Contraction Coupling / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018656:Muscle Fibers, Fast-Twitch / Q000166:cytology* / Q000502:physiology; D018657:Muscle Fibers, Slow-Twitch / Q000166:cytology* / Q000502:physiology; D018908:Muscle Weakness / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000196:embryology*; D020033:Protein Isoforms / Q000235:genetics
chemical_list: C529218:CACNA1S protein, mouse; D020746:Calcium Channels, L-Type; D020033:Protein Isoforms; D002118:Calcium
keywords: Mouse; Muscle fiber type specification; Skeletal muscle excitation-contraction coupling; Voltage-gated calcium channel