Why the study?
The hypertrophic cardiomyopathy-causing alpha-cardiac actin M305L mutation lies near residues confining tropomyosin to an inhibitory position, but its emergent pathological properties and disease mechanisms required resolution.
Does the α-cardiac actin M305L mutation alter actin flexibility and contractile regulation in muscle models?
Does the α-cardiac actin M305L mutation alter actin flexibility and contractile regulation in muscle models?
The α-cardiac actin M305L mutation reduces actin flexibility, leading to aberrant contractile inhibition and excessive force, highlighting the role of actin flexibility in muscle regulation and myopathy.
M305L actin distorts thin-filament regulation and promotes hypercontractility; leaves open whether actin flexibility is a therapeutic target in HCM.
Striated muscle contraction is regulated by the translocation of troponin-tropomyosin strands over the thin filament surface. Relaxation relies partly on highly-favorable, conformation-dependent electrostatic contacts between actin and tropomyosin, which position tropomyosin such that it impedes actomyosin associations. Impaired relaxation and hypercontractile properties are hallmarks of various muscle disorders. The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation lies near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here, we investigate M305L actin in vivo, in vitro, and in silico to resolve emergent pathological properties and disease mechanisms. Our data suggest the mutation reduces actin flexibility and distorts the actin-tropomyosin electrostatic energy landscape that, in muscle, result in aberrant contractile inhibition and excessive force. Thus, actin flexibility may be required to establish and maintain interfacial contacts with tropomyosin as well as facilitate its movement over distinct actin surface features and is, therefore, likely necessary for proper regulation of contraction.
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Viswanathan et al. (2020) studied this question.
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