Ca2+ Overload and Sarcoplasmic Reticulum Instability in tric-a Null Skeletal Muscle

• Published in: The Journal of biological chemistry Vol. 285; no. 48; pp. 37370 - 37376
• Main Authors: Zhao, Xiaoli, Yamazaki, Daiju, Park, Ki Ho, Komazaki, Shinji, Tjondrokoesoemo, Andoria, Nishi, Miyuki, Lin, Peihui, Hirata, Yutaka, Brotto, Marco, Takeshima, Hiroshi, Ma, Jianjie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.11.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Biological Transport; Ca super(2+)-transporting ATPase; Caffeine; Calcium; Calcium (intracellular); Calcium (reticular); Calcium - metabolism; Calcium Intracellular Release; Calcium permeability; Calcium signalling; Cardiac muscle; Chloride channels; Counter-ion Channel; Data processing; Deposits; Electron microscopy; Endoplasmic reticulum; Fatigue; Hydrogen; Ion Channels - deficiency; Ion Channels - genetics; Male; Membrane Biology; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction; Muscle, Skeletal - metabolism; Potassium; Potassium Channels; Rabbits; Ryanodine receptors; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum - genetics; Sarcoplasmic Reticulum - metabolism; Skeletal Muscle; Stress; Transgenic; Potassium Channels; Transgenic; Skeletal Muscle; Calcium Intracellular Release; Sarcoplasmic Reticulum; Counter-ion Channel
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.170084

The sarcoplasmic reticulum (SR) of skeletal muscle contains K+, Cl−, and H+ channels may facilitate charge neutralization during Ca2+ release. Our recent studies have identified trimeric intracellular cation (TRIC) channels on SR as an essential counter-ion permeability pathway associated with rapid Ca2+ 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 Ca2+ overload inside the SR with frequent formation of Ca2+ deposits compared with the wild type muscle. This elevated SR Ca2+ pool in the tric-a−/− muscle could be released by caffeine, whereas the elemental Ca2+ release events, e.g. osmotic stress-induced Ca2+ 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 Ca2+ 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 Ca2+ overload in SR, which in combination with the reduced counter-ion movement may lead to instability of Ca2+ movement across the SR membrane. The observed alternan behavior with the tric-a−/− muscle may reflect a skeletal muscle version of store overload-induced Ca2+ release that has been reported in the cardiac muscle under stress conditions.