Abstract
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.
Highlights
Striated muscle contraction is regulated by the translocation of troponin-tropomyosin strands over the thin filament surface
Hypertrophic cardiomyopathy (HCM) is a heterogeneous heart disorder, with a prevalence estimated at 1 in 200, that is characterized by asymmetric myocardial growth, thickening of the interventricular septum, hyperdynamic contractile properties during systole, and impaired relaxation during diastole[1,2,3]
Our findings are indicative of a gain-in-sarcomeric-function that results from a reduction in actin flexibility and concurrent destabilization of Tpm positioning along, and impaired movement over, thin filaments, which in humans may trigger HCM remodeling events
Summary
Striated muscle contraction is regulated by the translocation of troponin-tropomyosin strands over the thin filament surface. Much of the data are inconsistent, and in some cases contradictory, which confounds our understanding of the pathological basis of disease Extending these analyses, to determine the mutation’s effects in situ and/or in vivo, may help resolve how M305L actin elicits HCM and, importantly, highlight universal properties of muscle biology. The amino acid stretch containing K326, K328, E334, and a residue that protrudes out from the F-actin backbone, P333, likewise displays substantially restricted motion and aberrant intramolecular communication This could disrupt the formation of electrostatic interfacial contacts and the azimuthal stability of inhibitory Tpm positioning, as well as the unimpeded translocation of Tpm over the thin filament surface. Our findings are indicative of a gain-in-sarcomeric-function that results from a reduction in actin flexibility and concurrent destabilization of Tpm positioning along, and impaired movement over, thin filaments, which in humans may trigger HCM remodeling events
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