title: Ca2+ overload and sarcoplasmic reticulum instability in tric-a null skeletal muscle.
abstract: The sarcoplasmic reticulum (SR) of skeletal muscle contains K(+), Cl(-), and H(+) channels may facilitate charge neutralization during Ca(2+) release. Our recent studies have identified trimeric intracellular cation (TRIC) channels on SR as an essential counter-ion permeability pathway associated with rapid Ca(2+) release from intracellular stores. Skeletal muscle contains TRIC-A and TRIC-B isoforms as predominant and minor components, respectively. Here we test the physiological function of TRIC-A in skeletal muscle. Biochemical assay revealed abundant expression of TRIC-A relative to the skeletal muscle ryanodine receptor with a molar ratio of TRIC-A/ryanodine receptor ∼5:1. Electron microscopy with the tric-a(-/-) skeletal muscle showed Ca(2+) overload inside the SR with frequent formation of Ca(2+) deposits compared with the wild type muscle. This elevated SR Ca(2+) pool in the tric-a(-/-) muscle could be released by caffeine, whereas the elemental Ca(2+) release events, e.g. osmotic stress-induced Ca(2+) spark activities, were significantly reduced likely reflecting compromised counter-ion movement across the SR. Ex vivo physiological test identified the appearance of "alternan" behavior with isolated tric-a(-/-) skeletal muscle, i.e. transient and drastic increase in contractile force appeared within the decreasing force profile during repetitive fatigue stimulation. Inhibition of SR/endoplasmic reticulum Ca(2+ ATPase) function could lead to aggravation of the stress-induced alternans in the tric-a(-/-) muscle. Our data suggests that absence of TRIC-A may lead to Ca(2+) overload in SR, which in combination with the reduced counter-ion movement may lead to instability of Ca(2+) movement across the SR membrane. The observed alternan behavior with the tric-a(-/-) muscle may reflect a skeletal muscle version of store overload-induced Ca(2+) release that has been reported in the cardiac muscle under stress conditions.
authors.affiliation: Department of Physiology and Biophysics, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhao
authors.forename: Daiju
authors.initials: D
authors.lastname: Yamazaki
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Park
authors.forename: Shinji
authors.initials: S
authors.lastname: Komazaki
authors.forename: Andoria
authors.initials: A
authors.lastname: Tjondrokoesoemo
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nishi
authors.forename: Peihui
authors.initials: P
authors.lastname: Lin
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hirata
authors.forename: Marco
authors.initials: M
authors.lastname: Brotto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshima
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D007473:Ion Channels / Q000172:deficiency* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*
chemical_list: D007473:Ion Channels; C522221:TRIC-A protein, mouse; D002118:Calcium