Psychological stress has a pervasive influence on our lives. In many cases adapting to stress strengthens organisms, but chronic or severe stress is usually harmful. One surprising outcome of psychological stress is activation of an inflammatory response, resembling inflammation caused by infection or trauma. Excessive psychological stress and the consequential inflammation in the brain can increase susceptibility to psychiatric diseases, such as depression, and impair learning and memory, including in some patients with cognitive deficits. An emerging target to control detrimental outcomes of stress and inflammation is glycogen synthase kinase-3 (GSK3). GSK3 promotes inflammation, partly by regulating key transcription factors in the inflammation signaling pathway, and GSK3 can impair learning by promoting inflammation and by inhibiting long term potentiation (LTP). Drugs inhibiting GSK3 may prove beneficial for controlling mood and cognitive impairments caused by excessive stress and the associated neuroinflammation.

Myosin regulatory light chain (RLC) phosphorylation is important for cardiac muscle mechanics/function as well as for the Ca2+-troponin/tropomyosin regulation of muscle contraction. This study focuses on the arginine to glutamine (R58Q) substitution in the human ventricular RLC (MYL2 gene), linked to malignant hypertrophic cardiomyopathy in humans and causing severe functional abnormalities in transgenic R58Q mice, including inhibition of cardiac RLC phosphorylation. Using a phosphomimic recombinant RLC variant where the phosphorylation site Ser-15 was substituted with an aspartic acid (S15D) and placed in the background of R58Q, we aimed to assess whether we could rescue/mitigate R58Q-induced structural/functional abnormalities in vitro. We show rescue of several R58Q-exerted adverse phenotypes in S15D-R58Q-reconstituted porcine cardiac muscle preparations. A low level of maximal isometric force observed for R58Q- versus WT-reconstituted fibers was restored by S15D-R58Q. Significant beneficial effects were also observed on the Vmax of actin-activated myosin ATPase activity in S15D-R58Q versus R58Q-reconstituted myosin, along with its binding to fluorescently-labeled actin. We also report that R58Q promotes the OFF state of myosin, both in reconstituted porcine fibers and in transgenic mouse papillary muscles, thereby stabilizing the super-relaxed state (SRX) of myosin, characterized by a very low ATP turnover rate. Experiments in S15D-R58Q-reconstituted porcine fibers showed a mild destabilization of the SRX state, suggesting an S15D-mediated shift in disordered-relaxed (DRX)↔SRX equilibrium towards the DRX state of myosin. Our study shows that S15D-phosphomimic can be used as a potential rescue strategy to abrogate/alleviate the RLC mutation-induced phenotypes and is a likely candidate for therapeutic intervention in HCM patients.

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In this study, we focus on the molecular mechanisms associated with the A57G (Ala57‐to‐Gly57) mutation in myosin essential light chains (ELCs), found to cause hypertrophic cardiomyopathy (HCM) in humans and in mice. Specifically, we studied the effects of A57G on the super‐relaxed (SRX) state of myosin that may contribute to the hypercontractile cross‐bridge behavior and ultimately lead to pathological cardiac remodeling in transgenic Tg‐A57G mice. The disease model was compared to Tg‐WT mice, expressing the wild‐type human ventricular ELC, and analyzed against Tg‐Δ43 mice, expressing the N‐terminally truncated ELC, whose hearts hypertrophy with time but do not show any abnormalities in cardiac morphology or function. Our data suggest a new role for the N terminus of cardiac ELC (N‐ELC) in modulation of myosin cross‐bridge function in the healthy as well as in HCM myocardium. The lack of N‐ELC in Tg‐Δ43 mice was found to significantly stabilize the SRX state of myosin and increase the number of myosin heads occupying a low‐energy state. In agreement, Δ43 hearts showed significantly decreased ATP utilization and low actin‐activated myosin ATPase compared with A57G and WT hearts. The hypercontractile activity of A57G‐ELC cross‐bridges was manifested by the inhibition of the SRX state, increased number of myosin heads available for interaction with actin, and higher ATPase activity. Fiber mechanics studies, echocardiography examination, and assessment of fibrosis confirmed the development of two distinct forms of cardiac remodeling in these two ELC mouse models, with pathological cardiac hypertrophy in Tg‐A57G, and near physiologic cardiac growth in Tg‐Δ43 animals.