Ryanodine receptors mediate high intracellular Ca 2+ and some myocyte damage following eccentric contractions in rat fast-twitch skeletal muscle
Ryanodine receptors mediate high intracellular Ca 2+ and some myocyte damage following eccentric contractions in rat fast-twitch skeletal muscle
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Ryanodine 受体介导大鼠快肌骨骼肌偏心收缩后的高细胞内 Ca 2 和一些心肌细胞损伤
DOI：
10.1152/ajpregu.00166.2021
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Yutaka Kano
中科院分区：
文献类型：
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作者：
Ayaka Tabuchi;Yoshinori Tanaka;Ryo Takagi;Hideki Shirakawa;Tsubasa Shibaguchi;Takao Sugiura;David C Poole;Yutaka Kano
离心收缩（ECC）促进肌浆网（SR）释放胞质钙离子（Ca 2+）和细胞外间隙内流。Ca 2+是一种重要的信号信使，通过其空间和时间浓度（[Ca 2 +]i）动态调节多种细胞过程。我们假设：1）特定的空间/时间模式的肌细胞内Ca 2+动态预示着ECC后的肌肉损伤和2）这些动态将由Ryanodine受体（RyR）调节。[Ca2+]通过比率测量法（即，比率，R，340/380 nm激发）在ECC前和ECC后5和24 h（5 × 40收缩）用Fura-2进行体内生物成像。单独的大鼠组在ECC（+DAN）后立即接受RyR抑制剂丹曲林（DAN; 10 mg/kg ip）。通过对苏木精-伊红染色的肌肉切片进行组织学分析来评价肌肉损伤。与对照组（CONT，无ECC）相比，[Ca 2 +] i分布不均匀，高[Ca 2 +] i位点的总面积百分比增加（操作定义为R ≥ 1.39，即，术后5 h（CONT：14.0 ± 8.0; ECC 5 h：52.0 ± 7.4%，P < 0.01）。DAN可明显降低ECC后5 h的高[Ca 2 +] i面积（ECC 5 h + DAN：6.4 ± 3.1%，P < 0.01）和心肌细胞损伤（ECC 24 h，63.2 ± 1.0%; ECC 24 h + DAN：29.1 ± 2.2%，P < 0.01）。无论DAN与否，[Ca 2 +] i均出现时间和空间放大的波动（ECC vs. ECC + DAN，P> 0.05）。这些结果表明，RyR介导的局部高[Ca ~（2+）] i本身与肌肉损伤的程度有关，而[Ca ~（2+）] i波动是一种不依赖于RyR的现象。
Eccentric contractions (ECC) facilitate cytosolic calcium ion (Ca2+) release from the sarcoplasmic reticulum (SR) and Ca2+influx from the extracellular space. Ca2+is a vital signaling messenger that regulates multiple cellular processes via its spatial and temporal concentration ([Ca2+]i) dynamics. We hypothesized that1) a specific pattern of spatial/temporal intramyocyte Ca2+dynamics portends muscle damage following ECC and2) these dynamics would be regulated by the ryanodine receptor (RyR). [Ca2+]iin the tibialis anterior muscles of anesthetized adult Wistar rats was measured by ratiometric (i.e., ratio, R, 340/380 nm excitation) in vivo bioimaging with Fura-2 pre-ECC and at 5 and 24 h post-ECC (5 × 40 contractions). Separate groups of rats received RyR inhibitor dantrolene (DAN; 10 mg/kg ip) immediately post-ECC (+DAN). Muscle damage was evaluated by histological analysis on hematoxylin-eosin stained muscle sections. Compared with control (CONT, no ECC), [Ca2+]idistribution was heterogeneous with increased percent total area of high [Ca2+]isites (operationally defined asR≥ 1.39, i.e., ≥1 SD of mean control) 5 h post-ECC (CONT, 14.0 ± 8.0; ECC5h: 52.0 ± 7.4%,P< 0.01). DAN substantially reduced the high [Ca2+]iarea 5 h post-ECC (ECC5h + DAN: 6.4 ± 3.1%,P< 0.01) and myocyte damage (ECC24h, 63.2 ± 1.0%; ECC24h + DAN: 29.1 ± 2.2%,P< 0.01). Temporal and spatially amplified [Ca2+]ifluctuations occurred regardless of DAN (ECC vs. ECC + DAN,P> 0.05). These results suggest that the RyR-mediated local high [Ca2+]iitself is related to the magnitude of muscle damage, whereas the [Ca2+]ifluctuation is an RyR-independent phenomenon.