title: S100A1 promotes action potential-initiated calcium release flux and force production in skeletal muscle.
abstract: The role of S100A1 in skeletal muscle is just beginning to be elucidated. We have previously shown that skeletal muscle fibers from S100A1 knockout (KO) mice exhibit decreased action potential (AP)-evoked Ca(2+) transients, and that S100A1 binds competitively with calmodulin to a canonical S100 binding sequence within the calmodulin-binding domain of the skeletal muscle ryanodine receptor. Using voltage clamped fibers, we found that Ca(2+) release was suppressed at all test membrane potentials in S100A1(-/-) fibers. Here we examine the role of S100A1 during physiological AP-induced muscle activity, using an integrative approach spanning AP propagation to muscle force production. With the voltage-sensitive indicator di-8-aminonaphthylethenylpyridinium, we first demonstrate that the AP waveform is not altered in flexor digitorum brevis muscle fibers isolated from S100A1 KO mice. We then use a model for myoplasmic Ca(2+) binding and transport processes to calculate sarcoplasmic reticulum Ca(2+) release flux initiated by APs and demonstrate decreased release flux and greater inactivation of flux in KO fibers. Using in vivo stimulation of tibialis anterior muscles in anesthetized mice, we show that the maximal isometric force response to twitch and tetanic stimulation is decreased in S100A1(-/-) muscles. KO muscles also fatigue more rapidly upon repetitive stimulation than those of wild-type counterparts. We additionally show that fiber diameter, type, and expression of key excitation-contraction coupling proteins are unchanged in S100A1 KO muscle. We conclude that the absence of S100A1 suppresses physiological AP-induced Ca(2+) release flux, resulting in impaired contractile activation and force production in skeletal muscle.
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Prosser
authors.forename: Erick O
authors.initials: EO
authors.lastname: Hernández-Ochoa
authors.forename: Richard M
authors.initials: RM
authors.lastname: Lovering
authors.forename: Zoita
authors.initials: Z
authors.lastname: Andronache
authors.forename: Danna B
authors.initials: DB
authors.lastname: Zimmer
authors.forename: Werner
authors.initials: W
authors.lastname: Melzer
authors.forename: Martin F
authors.initials: MF
authors.lastname: Schneider
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002614:Chelating Agents / Q000378:metabolism; D003408:Cresols / Q000494:pharmacology; D004533:Egtazic Acid / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D005659:Fungicides, Industrial / Q000494:pharmacology; D015640:Ion Channel Gating / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011726:Pyridinium Compounds / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism*; D014966:Xanthenes / Q000378:metabolism
chemical_list: C089669:1-(3-sulfonatopropyl)-4-(beta-(2-(di-n-octylamino)-6-naphthyl)vinyl)pyridinium betaine; D000814:Aniline Compounds; D015415:Biomarkers; D002614:Chelating Agents; D003408:Cresols; C409648:Fluo 4; D005456:Fluorescent Dyes; D005659:Fungicides, Industrial; D011726:Pyridinium Compounds; D019837:Ryanodine Receptor Calcium Release Channel; D009418:S100 Proteins; C110294:S100A1 protein; D014966:Xanthenes; C006984:chlorocresol; D004533:Egtazic Acid; D002118:Calcium