Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM.
Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM.
复制标题
DOI：
10.3390/life13071463
复制
发表时间：
2023-06-28
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
本研究的重点是模拟肌球蛋白调节轻链（S15 D-RLC）N-末端的组成性磷酸化，作为肌球蛋白的基本（ELC，MYL 3基因）或调节（RLC，MYL 2基因）轻链突变引起的限制性（RCM）和扩张性（DCM）心肌病转基因（Tg）模型中突变诱导的心功能障碍的补救策略。在来自两种心肌病小鼠模型RCM-E143 K ELC和DCM-D94 A RLC的左心室乳头肌（LVPM）纤维中重构磷酸化模拟物S15 D-RLC，沿着它们相应的Tg-ELC和Tg-RLC野生型（WT）小鼠。S15 D-RLC在挽救心脏功能中的有益作用通过在两种心肌病模型中观察到的S15 D-RLC诱导的超松弛（SRX）状态的不稳定来证明。S15 D-RLC促进了从SRX状态到无序松弛（DRX）状态的转变，增加了易于与肌动蛋白相互作用并产生力的头部数量。此外，与用WT-RLC蛋白重建相比，用纤维重建的S15 D-RLC显示出显著更高的最大等长力/肌肉横截面。将磷酸模拟物S15 D-RLC的作用与Omecamtiv Mecarbil（OM）观察到的作用进行比较，Omecamtiv Mecarbil（OM）是一种肌球蛋白激活剂，可与心肌肌球蛋白的催化位点结合并增加心肌收缩力。在OM处理的纤维中观察到与S15 D-RLC重构制剂中类似的SRX ParticipDRX平衡位移。此外，在两种心肌病模型中，OM治疗导致每个肌纤维横截面的最大pCa 4力显著更高。我们的研究结果表明，用S15 D-RLC和OM治疗RCM-ELC和DCM-RLC小鼠均可改善肌球蛋白运动和心肌收缩功能。
This study focuses on mimicking constitutive phosphorylation in the N-terminus of the myosin regulatory light chain (S15D-RLC) as a rescue strategy for mutation-induced cardiac dysfunction in transgenic (Tg) models of restrictive (RCM) and dilated (DCM) cardiomyopathy caused by mutations in essential (ELC, MYL3 gene) or regulatory (RLC, MYL2 gene) light chains of myosin. Phosphomimetic S15D-RLC was reconstituted in left ventricular papillary muscle (LVPM) fibers from two mouse models of cardiomyopathy, RCM-E143K ELC and DCM-D94A RLC, along with their corresponding Tg-ELC and Tg-RLC wild-type (WT) mice. The beneficial effects of S15D-RLC in rescuing cardiac function were manifested by the S15D-RLC-induced destabilization of the super-relaxed (SRX) state that was observed in both models of cardiomyopathy. S15D-RLC promoted a shift from the SRX state to the disordered relaxed (DRX) state, increasing the number of heads readily available to interact with actin and produce force. Additionally, S15D-RLC reconstituted with fibers demonstrated significantly higher maximal isometric force per cross-section of muscle compared with reconstitution with WT-RLC protein. The effects of the phosphomimetic S15D-RLC were compared with those observed for Omecamtiv Mecarbil (OM), a myosin activator shown to bind to the catalytic site of cardiac myosin and increase myocardial contractility. A similar SRX↔DRX equilibrium shift was observed in OM-treated fibers as in S15D-RLC-reconstituted preparations. Additionally, treatment with OM resulted in significantly higher maximal pCa 4 force per cross-section of muscle fibers in both cardiomyopathy models. Our results suggest that both treatments with S15D-RLC and OM may improve the function of myosin motors and cardiac muscle contraction in RCM-ELC and DCM-RLC mice.
登录
查看更多内容
影响因子：
2.4
作者：
Schmid M;Toepfer CN
通讯作者：
Toepfer CN
影响因子：
37.8
作者：
Olson, TM;Karst, ML;Driscoll, DJ
通讯作者：
Driscoll, DJ
影响因子：
3.9
作者：
Muthu, Priya;Liang, Jingsheng;Szczesna-Cordary, Danuta
通讯作者：
Szczesna-Cordary, Danuta
影响因子：
5.8
作者：
Wang Y;Yuan CC;Kazmierczak K;Szczesna-Cordary D;Burghardt TP
通讯作者：
Burghardt TP
DOI：
10.1126/science.1200113
发表时间：
2011-03-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Malik FI;Hartman JJ;Elias KA;Morgan BP;Rodriguez H;Brejc K;Anderson RL;Sueoka SH;Lee KH;Finer JT;Sakowicz R;Baliga R;Cox DR;Garard M;Godinez G;Kawas R;Kraynack E;Lenzi D;Lu PP;Muci A;Niu C;Qian X;Pierce DW;Pokrovskii M;Suehiro I;Sylvester S;Tochimoto T;Valdez C;Wang W;Katori T;Kass DA;Shen YT;Vatner SF;Morgans DJ
通讯作者：
Morgans DJ