Diseased hearts to heal themselves in future

Diseased hearts to heal themselves in future

  10:08:00 AM    Science Lover

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Cellular reversion processes arise in diseases of the heart muscle, for example myocardial infarction and cardiomyopathy, which limit the fatal consequences for the organ. Scientists from the Max Planck Institute for Heart and Lung Research in Bad Nauheim and the Schüchtermann Klinik in Bad Rothenfelde have identified a protein which fulfils a central task in this reversion process by stimulating the regression of individual heart muscle cells into their precursor cells. It is now planned to improve the self-healing powers of the heart with the help of this protein.

Cellular regression in diseased heart tissue with the help
of oncostatin M: The image shows heart muscles under
the fluorescence microscope. The myofibrils are stained
red, the cell nuclei blue.
Credit: MPI for Heart and Lung Research

In order to regenerate damaged heart muscle as caused by a heart attack, for example, the damaged muscle cells must be replaced by new ones. The number of cells to be replaced may be considerable, depending on the extent of the damage caused. Simpler vertebrates like the salamander adopt a strategy whereby surviving healthy heart muscle cells regress into an embryonic state. This process, which is known as dedifferentiation, produces cells which contain a series of stem cell markers and re-attain their cell division activity. Thus, new cells are produced which convert, in turn, into heart muscle cells. The cardiac function is then restored through the remodelling of the muscle tissue.

An optimised repair mechanism of this kind does not exist in humans. Although heart stem cells were discovered some time ago, exactly how and to what extent they play a role in cardiac repair is a matter of dispute. It has only been known for a few years that processes comparable to those found in the salamander even exist in mammals.

Thomas Braun's research group at the Max Planck Institute for Heart and Lung Research in Bad Nauheim has now discovered the molecule responsible for controlling this dedifferentiation of heart muscle cells in mammals. The scientists initially noticed the high concentration of oncostatin M in tissue samples from the hearts of patients suffering from myocardial infarction. It was already known that this protein is responsible for the dedifferentiation of different cell types, among other things. The researchers therefore treated cultivated heart muscle cells with oncostatin M in the laboratory and were then able to trace the regression of the cells live under the microscope: "Based on certain changes in the cells, we were able to see that almost all heart muscle cells had been dedifferentiated within six days of treatment with oncostatin M," explains Braun. "We were also able to demonstrate the presence of various stem cell markers in the cells. This should be understood as an indicator that these cells had been switched to a repair mode."

Using a mouse infarct model, the Max Planck researchers succeeded in demonstrating that oncostatin M actually does stimulate the repair of damaged heart muscle tissue as presumed. One of the two test groups had been modified genetically in advance to ensure that the oncostatin M could not have any effect in these animals. "The difference between the two groups was astonishing. Whereas in the group in which oncostatin M could take effect almost all animals were still alive after four weeks, 40 percent of the genetically modified mice had died from the effects of the infarction," says Braun. The reason for this was that oncostatin M ensured clearly quantifiable better cardiac function in the unmodified animals.

The scientists in Bad Nauheim would now like to find a way of using oncostatin M in treatment. The aim is to strengthen the self-healing powers of the damaged heart muscle and to enable the restoration of cardiac function for the first time. The downside, however, is that oncostatin M was also observed to be counterproductive and exacerbated the damage in an experiment on a chronically diseased heart. "We believe that oncostatin M has considerable potential for efficiently healing damaged heart muscle tissue. What we now need is to be able to pinpoint the precise window of application to prevent any possible negative effects," says Braun.
More information: Thomas Kubin, Jochen Pöling, Sawa Kostin, Praveen Gajawada, Stefan Hein, Wolfgang Rees, Astrid Wietelmann, Minoru Tanaka, Holger Lörchner, Silvia Schimanski, Marten Szibor, Henning Warnecke, Thomas Braun: Oncostatin M Is a Major Mediator of Cardiomyocyte Dedifferentiation and Remodeling. Cell Stem Cell 9, 420, 2011

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Apple Ingredient Keeps Muscles Strong: Component of Apple Peels Found to Help Prevent Muscle Weakening in Mice

Apple Ingredient Keeps Muscles Strong: Component of Apple Peels Found to Help Prevent Muscle Weakening in Mice

  2:28:00 AM    Science Lover

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In search of a way to prevent the muscle wasting that comes with illness and aging, researchers have landed a natural compound that might just do the trick. The findings reported in the June issue of Cell Metabolism, a Cell Press publication, identify a component of apple peels as a promising new drug candidate for the widespread and debilitating condition that affects nearly everyone at one time or another.

Researchers have identified a component of apple 
peels that helps prevent muscle weakening in mice. 
(Credit: © Anyka / Fotolia)

"Muscle wasting is a frequent companion of illness and aging," said Christopher Adams of The University of Iowa, Iowa City. "It prolongs hospitalization, delays recoveries and in some cases prevents people from going back home. It isn't well understood and there is no medicine for it."

Motivated by the desire to change that, Adams' team first looked at what happens to gene activity in muscles under conditions that promote weakening. Those studies turned up 63 genes that change in response to fasting in both people and mice and another 29 that shift their expression in the muscles of both people who are fasting and those with spinal cord injury. Comparison of those gene expression signatures to the signatures of cells treated with more than 1300 bioactive small molecules led them to ursolic acid as a compound with effects that might counteract those of atrophy.

"Ursolic acid is an interesting natural compound," Adams said. "It's part of a normal diet as a component of apple peels. They always say that an apple a day keeps the doctor away…"



The researchers next gave ursolic acid to fasted mice. Those experiments showed that ursolic acid could protect against muscle weakening as predicted. When ursolic acid was added to the food of normal mice for a period of weeks, their muscles grew. Those effects were traced back to enhanced insulin signaling in muscle and to corrections in the gene signatures linked to atrophy.

Animals given ursolic acid also became leaner and had lower blood levels of glucose, cholesterol and triglycerides. The findings therefore suggest that ursolic acid may be responsible for some of the overall benefits of healthy eating.

"We know if you eat a balanced diet like mom told us to eat you get this material," Adams said. "People who eat junk food don't get this."

It is not yet clear whether the findings in mice will translate to human patients, Adams says, but his goal now is to "figure out if this can help people." If so, they don't yet know whether ursolic acid at levels that might be consumed as part of a normal diet might or might not be enough.

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Clues To Reversing Aging Of Human Muscle Discovered

Clues To Reversing Aging Of Human Muscle Discovered

  12:46:00 AM    Science Lover

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A study led by researchers at the University of California, Berkeley, has identified critical biochemical pathways linked to the aging of human muscle. By manipulating these pathways, the researchers were able to turn back the clock on old human muscle, restoring its ability to repair and rebuild itself.

Young, healthy muscle (left column) appears pink and red. In contrast, the old muscle is marked by scarring and inflammation, as evidenced by the yellow and blue areas. This difference between old and young tissue occurs both in the muscle's normal state and after two weeks of immobilization in a cast. Exercise after cast removal did not significantly improve old muscle regeneration; scarring and inflammation persisted, or worsened in many cases. 

(Credit: Photo by Morgan E. Carlson and Irina M. Conboy, UC Berkeley)

The findings will be reported in the Sept. 30 issue of the journal EMBO Molecular Medicine, a peer-reviewed, scientific publication of the European Molecular Biology Organization.

"Our study shows that the ability of old human muscle to be maintained and repaired by muscle stem cells can be restored to youthful vigor given the right mix of biochemical signals," said Professor Irina Conboy, a faculty member in the graduate bioengineering program that is run jointly by UC Berkeley and UC San Francisco, and head of the research team conducting the study. "This provides promising new targets for forestalling the debilitating muscle atrophy that accompanies aging, and perhaps other tissue degenerative disorders as well."

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