Protein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes.

Serine/threonine protein phosphatase 5 (PP5) is ubiquitously expressed in eukaryotic cells; however, its function in cardiomyocytes is unknown. Under basal conditions, PP5 is autoinhibited, but enzymatic activity rises upon binding of specific factors, such as the chaperone Hsp90. Here we show that PP5 binds and dephosphorylates the elastic N2B-unique sequence (N2Bus) of titin in cardiomyocytes. Using various binding and phosphorylation tests, cell-culture manipulation, and transgenic mouse hearts, we demonstrate that PP5 associates with N2Bus in vitro and in sarcomeres and is antagonistic to several protein kinases, which phosphorylate N2Bus and lower titin-based passive tension. PP5 is pathologically elevated and likely contributes to hypo-phosphorylation of N2Bus in failing human hearts. Furthermore, Hsp90-activated PP5 interacts with components of a sarcomeric, N2Bus-associated, mechanosensor complex, and blocks mitogen-activated protein-kinase signaling in this complex. Our work establishes PP5 as a compartmentalized, well-controlled phosphatase in cardiomyocytes, which regulates titin properties and kinase signaling at the myofilaments

Cardioprotection and lifespan extension by the natural polyamine spermidine

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease

Differential changes in titin domain phosphorylation increase myofilament stiffness in failing human hearts

In this article, Professor Franke asks and answers a seemingly simple question: why is sexual harassment a form of sex discrimination under Title VII of the Civil Rights Act of 1964? She argues that the link between sexual harassment and sex discrimination has been undertheorized b9 the Supreme Court. In the absence of a principled theory of the wrong of sexual harassment, Professor Franke argues that lower courts have developed a body of sexual harassment law that trivializes the legal norm against sex discrimination. After illustrating how the Supreme Court has not provided an adequate theory of sexual harassment as sex discrimination, she traces the theoretical arguments advanced by feminist scholars on behalf of a cause of action for sexual harassment under Title VII: 1) it violates formal equality principles; 2) its sexism lies in the fact that the conduct is sexual; and 3) sexual harassment is an example of the subordination of women by men. Professor Franke provides a critique of each of these accounts of sexual harassment, in part, by showing how each is unable to provide an account of whether same-sex sexual harassment should be actionable under Title VII. She argues that flaws in both the theory and the doctrine are amplified in the marginal cases of same-sex harassment. Professor Franke then argues that the discriminatory wrong of sexual harassment, between parties of different or same sexes, should be understood as a technology of sexism. That is, the sexism in sexual harassment lies in its power as a regulatory practice that feminizes women and masculinizes men, renders women sexual objects and men sexual subjects

Additional file 1: of Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function

This file contains Figures S1 to S5 and the corresponding figure legends. (PPTX 17980 kb