Mice missing BAG3 seem fine at birth, but when they start using their muscles to breathe and stand, muscle cells rapidly degenerate and cannot regenerate, says Dr. Shinichi Takayama, cell and molecular biologist at the Medical College of Georgia.
The finding illustrates BAG3’s importance in maintaining mature skeletal muscle, researchers say in the September issue of the American Journal of Pathology.
They hope it will lead to prevention of muscle atrophy that characterizes diseases such as muscular dystrophy, heart failure and a lesser-known condition called myofibril myopathy, which affects the tiniest muscle fibers. Dr. Takayama believes his BAG3 knockout is a model for the worst case of this rare disease.
“Basically we think that the degeneration starts because of usage of muscles, which should make them stronger,” Dr. Takayama says. Instead, cells previously dormant in utero start dying. “They cannot breathe, they cannot use their muscles and they die quickly,” he says of BAG3 knockout mice.
“When a muscle contraction happens, cytoskeletal degeneration occurs naturally,” he says. Interestingly, degeneration normally stimulates regeneration, but not in these mice. Instead cells take another option: when they can’t be fixed, they kill themselves.
This mass suicide in the absence of BAG3 is not a huge surprise. Dr. Takayama, the first to clone five members of the BAG family, says the proteins help regulate heat shock protein 70, which helps other proteins fold and function properly. The BAG family also has an anti-death function called antiapoptosis. Dr. Takayama is still dissecting the relationship between the anti-death function and BAG’s regulatory role with the heat shock protein. “If protein folding is not happening to a cell, that cell should die, so I think the two functions are related,” he says.
Without BAG3, researchers believe something goes wrong in the supporting structure of Z-discs, which help muscles contract. “The structure is tightly regulated by cytoskeletal proteins and something is wrong in the cytoskeleton of these mice,” he says. They found evidence of changes in the Z-discs that predate cell death, leading them to postulate that BAG3 is required for maintaining the integrity of Z-discs and other supporting components of the muscle cytoskeleton that helps strengthen and organize cells. “The muscle, in structure, seems normal at birth,” Dr. Takayama says. “But after four days, their Z-disc structure is disrupted.” Myofibrils, thin, cylindrical filaments that run the length of muscle cells, then begin to degenerate.
He first cloned BAG1 as an antiapoptotic protein more than 10 years ago while looking for a way to kill cancer cells. “BAG is one of the things that helps cancer cells survive,” says Dr. Takayama. In fact, BAG3 is highly expressed in cancer cells.
Last year, his group’s work published in Nature Neuroscience showed a BAG1 knockout experiences massive brain cell death as an embryo. He’s working on a mouse that over expresses BAG in muscle only, saying that should prevent cell death and atrophy.
The research was funded by the National Institutes of Health and the Muscular Dystrophy Association.
Toni Baker | EurekAlert!
Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute
Snap, Digest, Respire
20.01.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Life Sciences
20.01.2017 | Physics and Astronomy
20.01.2017 | Materials Sciences