Knockout mouse grows larger, but weaker, muscles: Finding has implications for age-related muscle loss

Main Category: Bones / Orthopedics
Also Included In: Seniors / Aging
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
Knockout mouse grows larger, but weaker, muscles: Finding has implications for age-related muscle loss

Although muscle cells did not reduce in size or number in mice lacking a protective antioxidant protein, they were weaker than normal muscle cells, researchers from the Barshop Institute for Longevity and Aging Studies at The University of Texas Health Science Center San Antonio found.

The scientists, who are faculty in the university's School of Medicine, are studying how oxidative stress in cells impacts sarcopenia - a loss of muscle mass and strength that occurs in all humans as they age.

Protein knocked out selectively

The antioxidant protein is called SOD1. The researchers developed mice that did not have SOD1 in their muscles, though it was still present in other types of cells. Then they asked the question: Is lack of SOD1 at the muscle enough to cause atrophy?

Surprisingly, the total muscle mass in this mouse was larger. "We think that lack of SOD1 could be priming the muscle to use all of its survival skills," said Holly Van Remmen, Ph.D., professor of cellular and structural biology in the School of Medicine and associate director for basic research at the Barshop Institute. "The muscle knows things aren't quite right. Its rescue mechanisms are pulled into play."

But even though the muscles were not atrophied, they were still weak.

Sarcopenia and oxidative stress

Sarcopenia in people has two components: loss of muscle mass and loss of function (weakness). This study supports the idea that oxidative stress has a role in these detrimental effects. If a way can be found to curb the effects, then healthier, more productive aging could result, Dr. Van Remmen said.

The oxidative stress theory of aging holds that oxidation from molecules called "free radicals" causes damage to cells over time, resulting in sarcopenia and other decline.

The study is described in The FASEB Journal. Future research will assess whether limiting oxidative stress can effect muscle regeneration, Dr. Van Remmen said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our bones / orthopedics section for the latest news on this subject.

This work was supported by U.S. National Institute on Aging grant AG-020591.

CuZnSOD gene deletion targeted to skeletal muscle leads to loss of contractile force but does not cause muscle atrophy in adult mice, The FASEB Journal, Yiqiang Zhang, Carol Davis, George K. Sakellariou, Yun Shi, Anna C. Kayani, Daniel Pulliam, Arunabh Bhattacharya, Arlan Richardson, Malcolm J. Jackson, Anne McArdle, Susan V. Brooks,_,1 and Holly Van Remmen, doi:10.1096/fj.13-228130

University of Texas Health Science Center at San Antonio

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Decellularized mouse heart beats again after regeneration with human heart precursor cells in Pitt project

Main Category: Cardiovascular / Cardiology
Also Included In: Biology / Biochemistry
Article Date: 15 Aug 2013 - 2:00 PDT Current ratings for:
Decellularized mouse heart beats again after regeneration with human heart precursor cells in Pitt project

For the first time, a mouse heart was able to contract and beat again after its own cells were stripped and replaced with human heart precursor cells, said scientists from the University of Pittsburgh School of Medicine. The findings, reported online in Nature Communications, show the promise that regenerating a functional organ by placing human induced pluripotent stem (iPS) cells - which could be personalized for the recipient - in a three-dimensional scaffold could have for transplantation, drug testing models and understanding heart development.

In the United States, one person dies of heart disease every 34 seconds, and more than 5 million people suffer from heart failure, meaning a reduced ability to pump blood, said senior investigator Lei Yang, Ph.D., assistant professor of developmental biology, Pitt School of Medicine. More than half of heart disease patients do not respond to current therapies and there is a scarcity of donor organs for transplant.

"Scientists have been looking to regenerative medicine and tissue engineering approaches to find new solutions for this important problem," Dr. Yang said. "The ability to replace a piece of tissue damaged by a heart attack, or perhaps an entire organ, could be very helpful for these patients."

For the project, the research team first "decellularized," or removed all the cells, from a mouse heart, a process that takes about 10 hours using a variety of agents. Then, they repopulated the remaining heart framework, or scaffold, with multipotential cardiovascular progenitor (MCP) cells. These replacement cells were produced by reverse engineering fibroblast cells from a small skin biopsy to make induced pluripotent stem cells and then treating the iPS cells with special growth factors to further induce differentiation.

"This process makes MCPs, which are precursor cells that can further differentiate into three kinds of cells the heart uses, including cardiomyocytes, endothelial cells and smooth muscle cells," Dr. Yang explained. "Nobody has tried using these MCPs for heart regeneration before. It turns out that the heart's extracellular matrix - the material that is the substrate of heart scaffold - can send signals to guide the MCPs into becoming the specialized cells that are needed for proper heart function."

After a few weeks, the mouse heart had not only been rebuilt with human cells, it also began contracting again, at the rate of 40 to 50 beats per minute, the researchers found. More work must be done to make the heart contract strongly enough to be able to pump blood effectively, and to rebuild the heart's electrical conduction system correctly so that the heart rate speeds up and slows down appropriately.

In the future, it might be possible to take a simple skin biopsy from a patient to derive personalized MCPs that can be used to seed a biologic scaffold and regenerate a replacement organ suitable for transplantation, Dr. Yang noted. The model also could be used as a lab-based method to preclinically test the effect of new drugs on the heart or to study how the fetal heart might develop.

"One of our next goals is to see if it's feasible to make a patch of human heart muscle," he added. "We could use patches to replace a region damaged by a heart attack. That might be easier to achieve because it won't require as many cells as a whole human-sized organ would."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cardiovascular / cardiology section for the latest news on this subject.

The project was funded by the University of Pittsburgh, the American Heart Association, and the National Science Council (Taiwan).

Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells

Nature Communications 4, Article number: 2307 doi:10.1038/ncomms3307

Tung-Ying Lu, Bo Lin, Jong Kim, Mara Sullivan, Kimimasa Tobita, Guy Salama & Lei Yang

University of Pittsburgh

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"Super Mouse" created in the UK may lead to novel treatment strategies for breast cancer

Main Category: Breast Cancer
Also Included In: Genetics
Article Date: 31 Jul 2013 - 0:00 PDT
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"Super Mouse" created in the UK may lead to novel treatment strategies for breast cancer

It appears tiny and inconsequential enough, but the "super mouse" - created by researchers at the University of Kentucky Markey Cancer Center some six years ago - has spawned plenty of new research into preventing and/or treating many types of cancer.

Back in 2007, cancer researcher Vivek Rangnekar and his team announced that they discovered a gene - known as Par-4 - that specifically kills cancer cells without killing normal cells. Rangnekar's team used this gene to develop cancer-resistant mice that become known as "super mice" for their ability to stay healthy and tumor-free compared to normal mice.

Since that initial discovery, researchers across the country have built upon Rangnekar's discovery, including a team at the University of Pennsylvania, who recently published findings on how Par-4 downregulation affects breast cancer recurrence.

In a new article for Cancer Cell, UK researchers including Rangnekar as well as Tripti Shrestha-Bhattarai and Nikhil Hebbar discuss a recent study and how its findings may lead to the development of novel treatment strategies for breast cancer.

Breast cancer is the second leading cause of cancer death in women. Even with treatment, one in five patients will relapse from the disease within 10 years, and patients who have triple-negative breast cancer have an especially high risk of both local and distant recurrence. Treatment for these aggressive cancers is difficult because they tend to be resistant to "standard of care" therapies.

The study performed by the UPenn team showed that in women who experienced breast cancer relapse, the Par-4 protein was suppressed. These low levels of Par-4 allowed the cancerous cells to survive and multiply even after a full course of treatment. Conversely, tumor cells that have high levels of Par-4 are eliminated by apoptosis (cell death) following treatment. These new findings may provide insight into deciding which patients are at the highest risk for cancer recurrence.

"What this tells us is that low Par-4 may act as a predictor of breast cancer recurrence," said Rangnekar, associate director for the UK Markey Cancer Center. "This is important, because although this group studied only breast cancer, their observations may be relevant to recurrence in a broad range of cancer types because Par-4 is a general tumor suppressor gene."

Using Par-4 levels as a biomarker prior to treatment - and knowing whether that patient is at an elevated risk of recurrence - would give physicians another tool to use in determining the best course of treatment. Additionally, their findings may provide the basis for the development of novel treatment strategies for breast cancer.

Other 'tumor suppressor' genes exist, says Rangnekar, but what makes Par-4 so special is that it is not mutated as frequently as other known suppressors, and it's "selective" in its actions in that Par-4 will only kill cancer cells and not normal cells. Par-4 can become 'suppressed' or inactivated, leading to tumor re-growth, but Par-4 can be 'activated' again - and one of the next major steps is developing a safe and effective way to activate Par-4 in the cancerous cells.

"If Par-4 is still present in the cells, the strategy should be to try and utilize that Par-4, so as to restore it's apoptotic function and bring about apoptosis of the cancer cells," Rangnekar said.

Researchers are still years away from being ready to test these theories in clinical trials, but Rangnekar says they have already begun looking at agents, both natural and synthetic, that may help restore the expression of Par-4 in human cells, allowing the cancerous cells to become susceptible to treatment. Each new study on Par-4 brings researchers one step closer to developing a powerful method for both treating and preventing many of the deadliest types of cancers.

The findings in the cancer-resistant mouse have stimulated several collaborative projects on Par-4 at UK. Several UK investigators are now examining the role of Par-4 in diverse types of tumors: recently, Rangnekar and UK cancer biologist and immunologist Subbarao Bondada were jointly funded by the National Institutes of Health to study the role of Par-4 in chronic lymphocytic leukemia; UK pathologist Craig Horbinski's group is investigating Par-4 in aggressive brain tumors called glioblastomas; and UK chemist David Watt and cancer biologist Chunming Liu are developing small molecules that can activate Par-4 and kill cancer cells.

"Our multi-disciplinary team, working together, uses a multi-faceted strategy in our research," Rangnekar said. "This allows us to gain a better understanding of the complexities of cancer in order to effectively kill recurrent tumor cells, especially those that have spread from their origin to distant tissue sites."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Par(-4)oxysm in Breast Cancer, Tripti Shrestha-Bhattarai, Nikhil Hebbar, Vivek M. Rangnekar, Cancer Cell, Volume 24, Issue 1, 3-5, 8 July 2013, doi: 10.1016/j.ccr.2013.06.010

University of Kentucky

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Innovation in mouse model helps researchers distinguish disease mechanisms and biomarkers

Main Category: Urology / Nephrology
Article Date: 30 Jul 2013 - 2:00 PDT Current ratings for:
Innovation in mouse model helps researchers distinguish disease mechanisms and biomarkers

A team led by researchers at the National Institutes of Health has overcome a major biological hurdle in an effort to find improved treatments for patients with a rare disease called methylmalonic acidemia (MMA). Using genetically engineered mice created for their studies, the team identified a set of biomarkers of kidney damage - a hallmark of the disorder - and demonstrated that antioxidant therapy protected kidney function in the mice.

Researchers at the National Human Genome Research Institute (NHGRI), part of NIH, validated the same biomarkers in 46 patients with MMA seen at the NIH Clinical Center. The biomarkers offer new tools for monitoring disease progression and the effects of therapies, both of which will be valuable in the researchers' design of clinical trials for this disease.

The discovery, reported in the July 29, 2013, advance online issue of the Proceedings of the National Academy of Sciences, paves the way for use of antioxidant therapy in a clinical trial for patients with MMA. It also illustrates the mechanisms by which dysfunction of mitochondria - the power generators of the cell - affects kidney disease. Mitochondrial dysfunction is a factor not only in rare disorders, such as MMA, but also in a wide variety of common conditions, such as obesity, diabetes and cancer.

MMA affects as many as one in 67,000 children born in the United States. It can have several different causes, all involving loss of function of a metabolic pathway that moderates levels of an organic compound called methylmalonic acid. Affected children are unable to properly metabolize certain amino acids consumed in their diet, which damages a number of organs, most notably the kidneys.

"Metabolic disorders like MMA are extremely difficult to manage because they perturb the delicate balance of chemicals that our bodies need to sustain health," said Daniel Kastner, M.D., Ph.D., NHGRI scientific director. "Given that every newborn in the United States is screened for a number of inherited metabolic disorders, including MMA, there is a critical need for better understanding of the disease mechanisms and therapies to treat them."

MMA is the most common organic acid disorder and invariably impairs kidney function, which can lead to kidney failure. The most common therapy is a restrictive diet, but doctors must resort to dialysis or kidney transplantation when the disease progresses. MMA patients also suffer from severe metabolic instability, failure to thrive, intellectual and physical disabilities, pancreatitis, anemia, seizures, vision loss and strokes.

"There are no definitive treatments for the management of patients with MMA," said Charles Venditti, M.D., Ph.D., senior author and investigator in the Organic Acid Research Section of NHGRI's Genetics and Molecular Biology Branch. "This study is the culmination of collaboration with the patient community. It uses mouse modelling, coupled with innovations in genomics and biochemical analyses, to derive new insights into the causes of renal injury in MMA. Our studies have improved our understanding of the basic biology underlying MMA, created a novel animal model for testing interventions and, now, led us to the promise of a new therapy."

The researchers performed the studies using mice bred to carry gene alterations that disrupt the production of the same mitochondrial enzyme that is defective in patients with MMA. These are called transgenic mice. The enzyme, called methylmalonyl-CoA mutase (MUT), is an important component of the chemical process that metabolizes organic acids, specifically methylmalonic acid.

By measuring gene expression in the transgenic mice using DNA microarrays, researchers discovered 50 biomarkers of gene expression that each indicated declining kidney function. DNA microarrays are silicon chips with many spots to which a given molecule may bind. In this case, the DNA microarrays were used to precisely generate, with the aid of a computer program, a profile of gene expression in a kidney cell.

The researchers chose one of the biomarkers, called lipocalin-2, to test how it correlated with kidney function in 46 MMA patients. Plasma levels of this biomarker rose with kidney deterioration in patients with MMA, and may serve as a valuable indicator of MMA kidney disease progression in the clinic.

"The detection of biomarkers through microarray technology is immensely helpful in pointing to downstream pathways affected by the defective MUT activity," said Irini Manoli, M.D., Ph.D., lead author and a physician scientist and staff clinician in NHGRI's Genetics and Molecular Biology Branch. "The biomarkers provide new plasma or serum tests to follow disease progression in our patients."

Having discovered these important biomarkers of kidney function, the authors turned to kidney physiology experts on their team to explore the structural changes that occur in MMA disease. They analyzed the rate at which the kidneys filter waste from the blood. Co-author and renal physiology expert Jurgen Schnermann, M.D., and members of his laboratory at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), also part of NIH, demonstrated the early and significant decrease in this rate in MMA mice.

With further studies, the researchers identified increased production of free radicals in tissues from the mice, as well as in the MMA patients. Detection of free radicals indicates chemical instability in cells, which the researchers sought to remedy with antioxidant therapy. After treating the mice with two forms of dietary antioxidants, the researchers observed that the biomarkers of kidney damage diminished and the faltering kidney filtration rate tapered off. The findings demonstrated that readily available antioxidants can significantly affect the rate of decline of kidney function in transgenic mice, which replicate the kidney disease of MMA.

"The next step will be to translate these findings to the clinic," Dr. Venditti said. "With a progressive disorder like MMA, we are hopeful that we have achieved a laboratory success that our patients will benefit from in the near future."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our urology / nephrology section for the latest news on this subject.

Irini Manoli, Justin R. Sysol, Lingli Li, Pascal Houillier, Caterina Garone, Cindy Wang, Patricia M. Zerfas, Kristina Cusmano-Ozog, Sarah Young, Niraj S. Trivedi, Jun Cheng, Jennifer L. Sloan, Randy J. Chandler, Mones Abu-Asab, Maria Tsokos, Abdel G. Elkahloun, Seymour Rosen, Gregory M. Enns, Gerard T. Berry, Victoria Hoffmann, Salvatore DiMauro, Jurgen Schnermann, and Charles P. Venditti, "Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia", Published online before print July 29, 2013, doi: 10.1073/pnas.1302764110

For information about the MMA clinical trial, go to ClinicalTrials.gov and search with NCT00078078.

Learn more about the study

NIH/National Human Genome Research Institute

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