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Wed 25 Jun 2008 04:00 AM

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Research matters

Researchers are beginning to understand exactly how various forms of exercise impact the heart.

News from the Harvard Medical School research community.

Heart healthMGH study shows how exercise changes structure and function of heart

For the first time, researchers are beginning to understand exactly how various forms of exercise impact the heart. Massachusetts General Hospital (MGH) investigators, in collaboration with the Harvard University Health Services, have found that 90 days of vigorous athletic training produces significant changes in cardiac structure and function and that the type of change varies with the type of exercise performed.

We have known for some time that the kidney can often repair itself after acute injury.

Their study appears in the April Journal of Applied Physiology.

"Most of what we know about cardiac changes in athletes and other physically active people comes from 'snapshots,' taken at one specific point in time. What we did in this first-of-a-kind study was to follow athletes over several months to determine how the training process actually causes change to occur," says Aaron Baggish, MD, a fellow in the MGH Cardiology Division and lead author of the study.

To investigate how exercise affects the heart over time, the MGH researchers enrolled two groups of Harvard University student athletes at the beginning of the fall 2006 semester.

One group was comprised of endurance athletes - 20 male and 20 female rowers - and the other, strength athletes - 35 male football players. Student athletes were studied while participating their normal team training, with emphasis on how the heart adapts to a typical season of competitive athletics.

Echocardiography studies - ultrasound examination of the heart's structure and function - were taken at the beginning and end of the 90-day study period. Participants followed the normal training regimens developed by their coaches and trainers, and weekly training activity was recorded. Endurance training included one- to three-hour sessions of on-water practice or use of indoor rowing equipment.

The strength athletes took part in skill-focused drills, exercises designed to improve muscle strength and reaction time, and supervised weight training. Participants also were questioned confidentially about the use of steroids, and any who reported such use were excluded from the study.

At the end of the 90-day study period, both groups had significant overall increases in the size of their hearts. For endurance athletes, the left and right ventricles - the chambers that send blood into the aorta and to the lungs, respectively - expanded. In contrast, the heart muscle of the strength athletes tended to thicken, a phenomenon that appeared to be confined to the left ventricle.

The most significant functional differences related to the relaxation of the heart muscle between beats - which increased in the endurance athletes but decreased in strength athletes, while still remaining within normal ranges.

"We were quite surprised by both the magnitude of changes over a relatively short period and by how great the differences were between the two groups of athletes," Baggish says. "The functional differences raise questions about the potential impact of long-term training, which should be followed up in future studies."

While this study looks at young athletes with healthy hearts, the information it provides may someday benefit heart disease patients. "The take-home message is that, just as not all heart disease is equal, not all exercise prescriptions are equal," Baggish explains.

"This should start us thinking about whether we should tailor the type of exercise patients should do to their specific type of heart disease. The concept will need to be studied in heart disease patients before we can make any definitive recommendations."

Diabetes careResearchers discover new effect for insulin

Researchers at the Joslin Diabetes Center have shown that insulin has a previously unknown effect that plays a role in ageing and lifespan, a finding that could ultimately provide a mechanism for gene manipulations that could help people live longer and healthier lives.

The paper, published in the March 21st issue of Cell, reports that insulin inhibits a master gene regulator protein known as SKN-1, and that increased SKN-1 activity increases lifespan.

SKN-1 controls what is called the Phase 2 detoxification pathway, a network of genes that defends cells and tissue against oxidative stress - damage caused by elevated levels of free radicals (byproducts of metabolism) - and various environmental toxins.

The new finding was demonstrated in experiments on the digestive system of C. elegans, a microscopic worm often used as a model organism.

"We've found something new that insulin does and it has to be considered when we think about how insulin is affecting our cells and bodies," said Dr. T. Keith Blackwell, senior investigator at Joslin and author of the paper.

"This has implications for basic biology since under some circumstances insulin may reduce defence against the damaging effects of oxidative stress more than we realise."The idea down the line is that fine-tuning the activity of SKN-1 may lead to increased resistance to chronic diseases and influence longevity, he said. The work could be important as it relates to diabetes and the many problems associated with the disease, particularly vascular and renal complications.

But, today's finding may be most important for what it teaches about ageing in general, he said.

"The major implication is that we have found something new that affects lifespan and ageing, and an important new effect that insulin and/or a related hormone called insulin-like growth factor-1 may have in some tissues," said Blackwell. "The implications go far beyond diabetes."

The major implication is that we have found something new that affects lifespan and ageing.

It has been known since the 1990s that insulin inhibits a gene regulator protein known as FOXO, important in diabetes metabolism, tumour suppression and stem cell maintenance.

FOXO controls a number of genes, including many involved in stress resistance. Studies in C. elegans showed that reduced insulin signalling boosted activity of a FOXO protein known as DAF-16, leading to greater stress resistance and longer life.

The new work places SKN-1 alongside FOXO as a second master gene regulator that is inhibited by insulin signalling and adds to the body of knowledge about insulin and its effects on gene pathways, stress resistance and ageing.

According to the paper, insulin's effect on SKN-1 occurs independently of its effect on DAF-16.

"You can manipulate the expression of SKN-1 and the worms live longer," said Blackwell, an Associate Professor of Pathology at Harvard Medical School and faculty member at the Harvard Stem Cell Institute.

The experiments will have to be repeated in mammals, where insulin and insulin-like growth factor-1 have a complex array of effects in different tissues. But, according to Blackwell, other findings in the C. elegans model have generally turned out to be applicable to mice and humans.

Blackwell's lab at Joslin is focusing on mechanisms of free radical resistance and ageing, and on gene regulation mechanisms in C. elegans stem cells with the idea of using this knowledge towards reprogramming human stem cells into insulin-producing cells.

Kidney healthThe search for a kidney stem cell: Researchers explore how an injured kidney may be able to repair itself using a mouse model

With the population ageing and rates of hypertension and diabetes higher than ever, there is a growing importance to understand how the kidney works to repair itself in order to guide the development of much needed future therapies.

Researchers at Brigham and Women's Hospital (BWH) examined cells in the kidney to determine which cells are responsible for generating repair. Their results are published in the March issue of Cell Stem Cell.

"There has not been a new therapy developed to treat kidney failure since dialysis was introduced in the 1950s," said Benjamin Humphreys, MD, PhD, in the Renal Division at BWH and lead author of the study.

"We have known for some time that the kidney can often repair itself after acute injury, and our goal is to understand this kidney repair process in hopes that it will lead us to pathways that can be used to guide the development of much needed clinical therapies."

In recent years there have been reports that an adult kidney stem cell may exist in the kidney and be responsible for repair. If an adult stem cell does exist though, researchers have yet to define its location.

Humphreys and colleagues genetically marked tubular epithelial cells in adult mice kidneys, but not other cells present between the tubules, where studies have suggested the kidney stem cell might reside.

Researchers then caused injury to the kidney, allowed the kidney to repair and tested whether the repaired epithelial cells still carried the genetic marker, or if they had been replaced by the non-marked cells adjacent to the tubules.

They found that repaired tubules retained the genetic marker, indicating that epithelial cells have the full capacity to repair themselves without any contribution from other adult kidney cell types. The research was performed in the Humphreys' Lab at BWH and Harvard University.Researchers conclude that if an adult stem cell does exist in the kidney, it is located within the tubular epithelial population, not outside of them. Further research is needed to determine whether all tubular cells have the same ability to generate growth, or if an adult stem cell with the capacity to repair is responsible for generating the growth.

"Defining the specific cell type responsible for repair after kidney injury is the first step toward designing regenerative therapies that ultimately will accelerate repair or slow chronic damage to the kidney," said Humphreys.

Cancer researchStudy helps explain fundamental process of tumour growth

Nearly 80 years ago, scientist Otto Warburg observed that cancer cells perform energy metabolism in a way that is different from normal adult cells. Many decades later, this observation was exploited by clinicians to better visualize tumours using PET (positron emission technology) imaging.

But it has not been known exactly how tumour cells perform this alternate metabolic feat, nor was it known if this process was essential for tumour growth.

Now, two papers appearing in the March 13 issue of the journal Nature help answer these questions. Led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, the papers find that the metabolic process that has come to be known as the Warburg effect is essential for tumours' rapid growth, and identifies the M2 form of pyruvate kinase (PKM2), an enzyme involved in sugar metabolism, as an important mechanism behind this process. This discovery could provide a target for the development of future cancer therapies.

"With this study we have answered a fundamental question regarding the ability of tumour cells to rapidly grow and proliferate," explains senior author Lewis Cantley, PhD, Director of the Cancer Center at BIDMC and Professor of Systems Biology at Harvard Medical School.

Metabolic regulation in rapidly growing tissues, such as foetal tissue or tumours, is different from that of normal adult tissue, Cantley explains. "Through aerobic glycolysis, or the Warburg effect, cancer cells produce energy by taking up glucose at much higher rates than other cells while, at the same time, using a smaller fraction of the glucose for energy production. This allows cancer cells to function more like foetal cells, promoting extremely rapid growth."

This unique metabolic property of cancer cells has led to the success of PET imaging as a means of cancer detection; because radioactive glucose injected into patients prior to the imaging exam is preferentially taken up by glucose-hungry tumour cells, the areas of high glucose uptake are displayed dramatically on the PET scan.

Using a novel proteomic screen to identify new phosphotyrosine binding proteins, Cantley and his colleagues first determined that PKM2 can bind to phosphotyrosine-containing peptides.

"We observed that in contrast to the forms of pyruvate kinase found in most normal adult tissues, only PKM2, which is found in foetal cells, interacted with phosphotyrosine," explains Cantley. "This finding was particularly interesting because previous reports had shown that this M2 form was the pyruvate kinase form used by all cancer cells."

In order to understand the implications of this discovery, Cantley and his co-authors next embarked upon experiments to evaluate the importance of PKM2 to cancer cells.

Reasoning that tumour tissue switches pyruvate kinase expression from an adult M1 isoform to the embryonic M2 isoform, they performed immunoblotting and immunohistochemistry analysis of numerous cancer cell lines, breast cancer models and human colon cancer, confirming that PKM2 was the only form of pyruvate kinase found in cancerous tissue.

The authors then knocked down PKM2 expression in human cancer cell lines and expressed the adult M1 form instead. This switch from the foetal M2 form to the adult M1 isoform led to reduced lactate production and increased oxygen consumption - a reversal of the Warburg effect.

"We were able to show that only cells which express the M2 form of pyruvate kinase - and metabolize glucose in the way described by Otto Warburg 80 years ago - had the ability to form tumours in mice," notes Cantley.

In addition, the investigators demonstrated that it is the ability of PKM2 to interact with phosphotyrosine that enables this form of pyruvate kinase to promote the unique glucose metabolism seen in cancer cells, thereby allowing these cells to make tumours in vivo.The findings are consistent with the idea that tumour cells preferentially use glucose for purposes other than making adenosine triphosphate (ATP), the energy currency used by normal cells.

"We suspect that this mechanism evolved to ensure that foetal tissues only use glucose for growth when they are activated by appropriate growth factor receptor protein-tyrosine kinases," adds Cantley.

"By re-expressing PKM2, cancer cells acquire the ability to use glucose for anabolic processes. Because PKM2 is found in all of the cancer cells that we have examined, because it is not found in most normal adult tissues, and because it is critical for tumour formation, this form of pyruvate kinase is a possible target for cancer therapy," he adds.

Melanoma therapyReport describes first targeted therapy to produce remission of metastatic melanoma

In a demonstration that even some of the most hard-to-treat tumours may one day succumb to therapies aimed at molecular "weak points," researchers at Dana-Farber Cancer Institute report the first instance in which metastatic melanoma has been driven into remission by a targeted therapy.

The report, published in the April 20 issue of the Journal of Clinical Oncology, describes the case of a 79-year-old woman with melanoma tumours in several parts of her abdomen. When lab tests showed the tumour cells carried an abnormality in a gene called KIT, the patient enrolled in a clinical trial involving Gleevec (Imatinib), a drug known to target that gene.

Four weeks after beginning therapy, imaging exams showed a dramatic reduction in tumour size and metabolism: two of the tumour masses had disappeared and several others had shrunken considerably. Four months later, the tumours were still in check, and today, nine months after the start of therapy, she continues to take the drug and her condition remains stable.

"This is the first proof of principle that we can find an Achilles' heel in melanoma" - a gene critical to tumour cell growth and proliferation - "and, by targeting that gene with a drug, cause the cell to die," says the study's lead author, Stephen Hodi, MD, of Dana-Farber. "It is especially exciting because there haven't been any effective treatments for melanoma patients with metastatic disease."

Although the report involves just one patient, it should inject new confidence in the fight against melanoma, Hodi says. Because previous research has failed to find any genetic Achilles' heels capable of shutting down melanoma cell growth, some researchers had speculated that none may exist for such cells. The discovery of one suggests there may be others.

KIT mutations are found in only a small percentage of melanomas, so Imatinib does not represent a universal treatment for the disease, Hodi explains. Recent studies have found KIT mutations in 11 percent of acral melanomas (which arise in skin without hair follicles, such as that of the palms, foot soles, and nail beds, and account for 5 percent of all melanomas), 21 percent of mucosal melanomas (which arise in the mucous membranes of some organs), and 17 percent of melanomas arising in chronically sun-damaged skin. For patients with these conditions, particularly those who carry a mutation in a particular section of the gene, Imatinib may well prove beneficial.

Imatinib's effectiveness against tumours with KIT mutations was first demonstrated in gastrointestinal stromal tumours (GISTs), a relatively rare malignancy of the digestive tract.

An estimated 75-80 percent of GISTs have KIT mutations, and Imatinib has caused such tumours to stabilize or retreat in 75-90 percent of patients receiving it. In most of these patients, however, tumours eventually begin growing again as they become resistant to the drug.

The KIT mutation in the patient described in the study involved a protein-coding section of the gene where DNA was duplicated. This section, known as the "juxtamembrane domain," is the most frequent site of mutation in GIST, and is associated with a strong tumour response to Imatinib.

"Dramatic remissions in metastatic melanoma are something that, as physicians, we've rarely seen," Hodi remarks.

"Confirming these results will require enrolling additional patients in clinical trials - something we're actively working to accomplish."

Research Matters brings together selected research being conducted at Harvard Medical School's 18 affiliated institutions. For more information, visit the Harvard Medical School website at:

This article is provided courtesy of Partners Harvard Medical International.

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