Influence of 2,3-Butanedione-Monoxime on the Interaction of Myosin with Actin in Healthy and in Congenital Myopathy

Author:

Andreeva D. D.1,Rysev N. A.1,Borovikov Y. S.1,Karpicheva O. E.1

Affiliation:

1. Institute of Cytology, Russian Academy of Sciences

Abstract

Congenital myopathies are a heterogeneous group of human skeletal muscle disorders characterized by muscle hypotonia and weakness. Myopathies have a wide range of clinical phenotypes, which makes it extremely difficult to develop approaches to their treatment. There are several pharmacological agents in clinical use or under clinical investigation for the treatment of cardiomyopathies whose mechanism of action can be used to treat congenital myopathies as well. One such agent is 2,3-butanedione-monoxime (BDM), a noncompetitive inhibitor of myosin ATPase activity used to suppress acute myocardial injury. The molecular mechanisms of inhibition of myosin by BDM in skeletal muscle have not been studied, therefore the aim of this work was to estimate the effect of BDM on the interaction of myosin with actin in the modeling of several ATPase stages in skeletal muscle fiber, in order to assess the prospects for the use of BDM for the treatment of congenital myopathies. We found that BDM enhances the rigidity of myosin binding to actin when modeling weak binding forms of these muscle proteins, which can slow down the transition of actomyosin from the AM ∙ ADP ∙ Pi to the AM ∙ ADP state and is one of the reasons for the decrease in myosin ATPase activity in the presence of BDM. When modeling successive stages of the ATPase cycle using ADP, AMPPNP, ATPγS, and ATP, the myosin heads gradually switch to a state of weak interaction with actin. In the presence of the regulatory proteins tropomyosin and troponin in the muscle fiber, BDM does not affect the formation of a weak form of actomyosin binding, but increases the number of myosin heads essential for force generation. BDM can be used to increase the efficiency of myosin conformational rearrangements in the presence of tropomyosin with the R90P mutation associated with congenital myopathy, since this reagent increases the number of myosin heads in the muscle fiber capable of effective conformational rearrangements in the ATPase cycle and partially inhibits the pathological effects of the mutation.

Publisher

The Russian Academy of Sciences

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3