Search

Your search keyword '"Johanna K. Freundt"' showing total 6 results
Start Over Author "Johanna K. Freundt"
6 results on '"Johanna K. Freundt"'

1. Histone deacetylase inhibition by Entinostat for the prevention of electrical and structural remodeling in heart failure

Author

Johanna K. Freundt, Gerrit Frommeyer, Tilmann Spieker, Fabian Wötzel, Jochen Schulze Grotthoff, Jörg Stypmann, Georg Hempel, Michael Schäfers, Andreas H. Jacobs, Lars Eckardt, and Philipp S. Lange

Subjects
HDAC, Entinostat, Arrhythmias, Remodeling, Fibrosis, Therapeutics. Pharmacology, RM1-950, Toxicology. Poisons, RA1190-1270
Abstract

Abstract Background The development of heart failure is accompanied by complex changes in cardiac electrophysiology and functional properties of cardiomyocytes and fibroblasts. Histone deacetylase (HDAC) inhibitors hold great promise for the pharmaceutical therapy of several malignant diseases. Here, we describe novel effects of the class I HDAC inhibitor Entinostat on electrical and structural remodeling in an in vivo model of pacing induced heart failure. Methods Rabbits were implanted a pacemaker system, subjected to rapid ventricular pacing and treated with Entinostat or placebo, respectively. Following stimulation, rabbit hearts were explanted and subsequently subjected to electrophysiological studies and further immunohistological analyses of left ventricles. Results In vivo, rapid ventricular stimulation caused a significant prolongation of monophasic action potential duration compared to sham hearts (from 173 ± 26 ms to 250 ± 41 ms; cycle length 900 ms; p

Published
2019
Full Text
View/download PDF

2. Graded titin cleavage progressively reduces tension and uncovers the source of A-band stability in contracting muscle

Author

Yong Li, Anthony L Hessel, Andreas Unger, David Ing, Jannik Recker, Franziska Koser, Johanna K Freundt, and Wolfgang A Linke

Subjects
skeletal muscle fibers, mechanics, ultrastructure, elasticity, contraction, immunocytochemistry, Medicine, Science, Biology (General), QH301-705.5
Abstract

The giant muscle protein titin is a major contributor to passive force; however, its role in active force generation is unresolved. Here, we use a novel titin-cleavage (TC) mouse model that allows specific and rapid cutting of elastic titin to quantify how titin-based forces define myocyte ultrastructure and mechanics. We show that under mechanical strain, as TC doubles from heterozygous to homozygous TC muscles, Z-disks become increasingly out of register while passive and active forces are reduced. Interactions of elastic titin with sarcomeric actin filaments are revealed. Strikingly, when titin-cleaved muscles contract, myosin-containing A-bands become split and adjacent myosin filaments move in opposite directions while also shedding myosins. This establishes intact titin filaments as critical force-transmission networks, buffering the forces observed by myosin filaments during contraction. To perform this function, elastic titin must change stiffness or extensible length, unveiling its fundamental role as an activation-dependent spring in contracting muscle.

Published
2020
Full Text
View/download PDF

4. Titin as a force-generating muscle protein under regulatory control

Author

Johanna K. Freundt and Wolfgang A. Linke

Subjects
0301 basic medicine, animal structures, Physiology, Muscle Proteins, macromolecular substances, Sarcomere, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Myocyte, Animals, Humans, Connectin, Muscle, Skeletal, Mechanical Phenomena, Muscle protein, biology, Chemistry, Molecular spring, musculoskeletal system, Cell biology, Actin Cytoskeleton, 030104 developmental biology, Regulatory control, biology.protein, Phosphorylation, Titin, 030217 neurology & neurosurgery, Function (biology), Signal Transduction
Abstract

Titin has long been recognized as a mechanical protein in muscle cells that has a main function as a molecular spring in the contractile units, the sarcomeres. Recent work suggests that the titin spring contributes to muscle contraction in a more active manner than previously thought. In this review, we highlight this property, specifically the ability of the immunoglobulin-like (Ig) domains of titin to undergo unfolding-refolding transitions when isolated titin molecules or skeletal myofibrils are held at physiological force levels. Folding of titin Ig domains under force is a hitherto unappreciated, putative source of work production in muscle cells, which could work in synergy with the actomyosin system to maximize the energy delivered by a stretched, actively contracting muscle. This review also focuses on the mechanisms shown to modulate titin-based viscoelastic forces in skeletal muscle cells, including chaperone binding, titin oxidation, phosphorylation, Ca2+binding, and interaction with actin filaments. Along the way, we discuss which of these modulatory mechanisms might contribute to the phenomenon of residual force enhancement relevant for eccentric muscle contractions. Finally, a brief perspective is added on the potential for the alterations in titin-based force to dynamically alter mechano-chemical signaling pathways in the muscle cell. We conclude that titin from skeletal muscle is a determinant of both passive and active tension and a bona fide mechanosensor, whose stiffness is tuned by various independent mechanisms.

Published
2018

Catalog

Books, media, physical & digital resources
See catalog results