Key result
Actin-binding compounds differentially affected the transition of G-actin to F-actin and ATPase activity in skeletal versus cardiac muscle isoforms and myofibrils.
Why the study?
Compounds targeting muscle function rarely target actin due to high conservation, but identifying agents that differentially affect skeletal and cardiac muscle is clinically desirable.
Do actin-binding compounds differentially affect skeletal and cardiac muscle actins and myofibrils?
Do actin-binding compounds differentially affect skeletal and cardiac muscle actins and myofibrils?
Structural and biochemical assays can identify actin-binding compounds that differentially affect skeletal and cardiac muscles, enabling future screening for muscle-specific therapeutics.
May enable cardiac- vs skeletal-muscle selective modulation; leaves open clinical utility pending in vivo validation.
Actin's interactions with myosin and other actin-binding proteins are essential for cellular viability in numerous cell types, including muscle. In a previous high-throughput time-resolved FRET (TR-FRET) screen, we identified a class of compounds that bind to actin and affect actomyosin structure and function. For clinical utility, it is highly desirable to identify compounds that affect skeletal and cardiac muscle differently. Because actin is more highly conserved than myosin and most other muscle proteins, most such efforts have not targeted actin. Nevertheless, in the current study, we tested the specificity of the previously discovered actin-binding compounds for effects on skeletal and cardiac α-actins as well as on skeletal and cardiac myofibrils. We found that a majority of these compounds affected the transition of monomeric G-actin to filamentous F-actin, and that several of these effects were different for skeletal and cardiac actin isoforms. We also found that several of these compounds affected ATPase activity differently in skeletal and cardiac myofibrils. We conclude that these structural and biochemical assays can be used to identify actin-binding compounds that differentially affect skeletal and cardiac muscles. The results of this study set the stage for screening of large chemical libraries for discovery of novel compounds that act therapeutically and specifically on cardiac or skeletal muscle.
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Guhathakurta et al. (2020) studied this question. Actin-binding compounds was evaluated on Transition of monomeric G-actin to filamentous F-actin and ATPase activity. Actin-binding compounds differentially affected the transition of G-actin to F-actin and ATPase activity in skeletal versus cardiac muscle isoforms and myofibrils.
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