Archive for the ‘Hormomes’ Category

By studying the genes of a German child born with unusually well developed muscles, an international research team has discovered the first evidence that the gene whose loss makes “mighty mice” also controls muscle growth in people.

Writing in the June 24 issue of the New England Journal of Medicine, German neurologist Markus Schuelke, M.D., and the team show that the child’s extra-large muscles are due to an inherited mutation that effectively silences the myostatin gene, proving that its protein normally keeps muscle development in check in people.

People with muscle-wasting conditions such as muscular dystrophy, and others just wanting to “bulk up,” have eagerly followed work on myostatin, hoping for a way to counteract the protein’s effects in order to build or rebuild muscle mass. But while research with mice has continued to reveal myostatin’s role and the effects of interfering with it, no one knew whether any of the results would be relevant to humans.

“This is the first evidence that myostatin regulates muscle mass in people as it does in other animals,” says Se-Jin Lee, M.D., Ph.D., professor of molecular biology and genetics in the Institute for Basic Biomedical Sciences at Johns Hopkins and co-author on the study. “That gives us a great deal of hope that agents already known to block myostatin activity in mice may be able to increase muscle mass in humans, too.”

Lee and his team discovered in 1997 that knocking out the myostatin gene led to mice that were twice as muscular as their normal siblings, lending them the moniker “mighty mice.” Later, others showed that naturally bulky cattle, such as Belgian Blues, got their extra muscles from lack of myostatin, too.

An unusual opportunity to examine myostatin’s role in humans arose when Schuelke examined a newborn baby boy, almost five years ago, and was struck by the visible muscles on the infant’s upper legs and upper arms. When ultrasound proved that the muscles were roughly twice as large as other infants’, but otherwise normal, Schuelke realized that a naturally occurring mutation in the child’s myostatin gene might be the cause.

Sequencing the myostatin gene from the boy and his mother, who had been a professional athlete, revealed a single change in the building blocks of the gene’s DNA. Surprisingly, the change was not in the gene regions that correspond to the resulting protein, but in the intervening regions that are used only to create protein-making instructions, thus changing the gene’s protein-building message.

“The mutation caused the gene’s message, the messenger RNA, to be wrong,” says Hopkins

neurologist Kathryn Wagner, M.D., Ph.D., who tested the genetic mutation’s effect in laboratory studies. “If the message had been used to make a protein, it would be much shorter than it should be. But we think the process doesn’t even get that far; instead the cells just destroy the message.”

Co-authors from Wyeth Research, Cambridge, Mass., analyzed samples of the child’s blood for evidence of the myostatin protein and found none. “Both copies of the child’s myostatin gene have this mutation, so little if any of the myostatin protein is made,” says Schuelke. “As a result, he has about twice the muscle mass of other children.”

Completely lacking myostatin, the boy is stronger than other children his age, and fortunately has no signs of problems with his heart so far, Schuelke says. But he adds that it’s impossible to know whether the lack of myostatin in that crucial muscle might lead to problems as the boy gets older.

While other family members — the boy’s mother and her brother, father and grandfather — were also reported to have been usually strong, only the mother’s DNA was available for analysis along with her son’s. Schuelke discovered that only one copy of the mother’s myostatin gene had the mutation found in both copies of her son’s myostatin gene. (We have two copies of each gene; one inherited from the mother and one inherited from the father.)

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Article adapted by MD Sports Weblog from original press release.
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 Contact: Joanna Downer
Johns Hopkins Medical Institutions

 

The Johns Hopkins researchers were funded by the National Institutes of Health and the Muscular Dystrophy Association. The German researchers were funded by the parents’ self-help group (Helft dem muskelkranken Kind).

Authors on the paper are Schuekle, Christoph Hubner, Thomas Riebel and Wolfgang Komen of Charite, University Medical Center Berlin, Germany; Wagner and Lee of Johns Hopkins; Leslie Stolz and James Tobin of Wyeth Research, Cambridge, Ma.; and Thomas Braun of Martin-Luther-University, Halle-Wittenberg, Germany.

*Under a licensing agreement between MetaMorphix Inc. and The Johns Hopkins University, Lee is entitled to a share of royalty received by the University on sales of products described in this article. Lee also is entitled to a share of sublicensing income from arrangements between MetaMorphix and American Home Products (Wyeth Ayerst Laboratories) and Cape Aquaculture Technologies. Lee and the University own MetaMorphix Inc. stock, which is subject to certain restrictions under University policy. Lee owns Cape Aquaculture Technologies stock, which is subject to certain restrictions under University policy. Lee has served as a paid consultant to MetaMorphix Inc. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

And it increases endurance to run a mile and decreases inflammation

The Salk Institute scientist who earlier discovered that enhancing the function of a single protein produced a mouse with an innate resistance to weight gain and the ability to run a mile without stopping has found new evidence that this protein and a related protein play central roles in the body’s complex journey to obesity and offer a new and specific metabolic approach to the treatment of obesity related disease such as Syndrome X (insulin resistance, hyperlipidemia and atherosclerosis).

Dr. Ronald M. Evans, a Howard Hughes Medical Investigator at The Salk Institute’s Gene Expression Laboratory, presented two new studies (date) at Experimental Biology 2005 in the scientific sessions of the American Society for Biochemistry and Molecular Biology. The studies focus on genes for two of the nuclear hormone receptors that control broad aspects of body physiology, including serving as molecular sensors for numerous fat soluble hormones, Vitamins A and D, and dietary lipids.

The first study focuses on the gene for PPARd, a master regulator that controls the ability of cells to burn fat. When the “delta switch” is turned on in adipose tissue, local metabolism is activated resulting in increased calorie burning. Increasing PPARd activity in muscle produces the “marathon mouse,” characterized by super-ability for long distance running. Marathon mice contain altered muscle composition, which doubles its physical endurance, enabling it to run an hour longer than a normal mouse. Marathon mice contain increased levels of slow twitch (type I) muscle fiber, which confers innate resistance to weight gain, even in the absence of exercise.

Additional work to be reported at Experimental Biology looks at another characteristic of PPARd: its role as a major regulator of inflammation. Coronary artery lesions or atherosclerosis are thought to be sites of inflammation. Dr. Evans found that activation of PPARd suppresses the inflammatory response in the artery, dramatically slowing down lesion progression. Combining the results of this new study with the original “marathon mouse” findings suggests that PPARd drugs could be effective in controlling atherosclerosis by limiting inflammation and at the same time promoting improved physical performance.

Dr. Evans says he is very excited about the therapeutic possibilities related to activation of the PPARd gene. He believes athletes, especially marathon runners, naturally change their muscle fibers in the same way as seen in the genetically engineered mice, increasing levels of fat-burning muscle fibers and thus building a type of metabolic ‘shield” that keeps them from gaining weight even when they are not exercising.

But athletes do it through long periods of intensive training, an approach unavailable to patients whose weight or medical problems prevent them from exercise. Dr. Evans believes activating the PPARd pathway with drugs (one such experimental drug already is in development to treat people with lipid metabolism) or genetic engineering would help enhance muscle strength, combat obesity, and protect against diabetes in these patients.

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Article adapted by MD Sports Weblog from original press release.
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Contact: Sarah Goodwin
Federation of American Societies for Experimental Biology

When given extra shots of the plant steroid brassinolide, plants “pump up” like major league baseball players do on steroids. Tracing brassinolide’s signal deep into the cell’s nucleus, researchers at the Salk Institute for Biological Studies have unraveled how the growth-boosting hormone accomplishes its job at the molecular level.The Salk researchers, led by Joanne Chory, a professor in the Plant Molecular and Cellular Biology Laboratory and a Howard Hughes Medical Institute investigator, published their findings in this week’s journal Nature.

“The steroid hormone brassinolide is central to plants’ growth. Without it, plants remain extreme dwarfs. If we are going to understand how plants grow, we need to understand the response pathway to this hormone,” says Chory. “This study clarifies what’s going on downstream in the nucleus when brassinolide signals a plant cell to grow.”

Brassinolide, a member of a family of plant hormones known as brassinosteroids, is a key element of plants’ response to light, enabling them to adjust growth to reach light or strengthen stems. Exploiting its potent growth-promoting properties could increase crop yields or enable growers to make plants more resistant to drought, pathogens, and cold weather.

Unfortunately, synthesizing brassinosteroids in the lab is complicated and expensive. But understanding how plant steroids work at the molecular level may one day lead to cheap and simple ways to bulk up crop harvests.

Likewise, since low brassinolide levels are associated with dwarfism, manipulating hormone levels during dormant seasons may allow growers to control the height of grasses, trees or other plants, thereby eliminating the need to constantly manicure gardens.

Based on earlier studies, the Salk researchers had developed a model that explained what happens inside a plant cell when brassinolide signals a plant cell to start growing.

But a model is just a model. Often evidence in favor of a particular model is indirect and could support multiple models. Describing the components of the signaling cascade that relays brassinolide’s message into a cell’s nucleus, postdoctoral researcher and lead author of the study Grégory Vert, now at the Centre national de la recherche scientifique (CNRS) in Montpellier, France, said, “All the players are old acquaintances and we knew from genetic studies that they were involved in this pathway. But when we revisited the old crew it became clear that we had to revise the original model.”

When brassinosteroids bind a receptor on the cell’s surface, an intracellular enzyme called BIN2 is inactivated by an unknown mechanism. Previously, investigators thought that inactivation of BIN2, which is a kinase, freed a second protein known as BES1 from entrapment in the cytoplasm, the watery compartment surrounding a cell’s nucleus, and allowed it to migrate or “shuttle” into the nucleus where it tweaked the activity of genes regulating plant growth.

A closer inspection, however, revealed that BIN2 resides in multiple compartments of a cell, including the nucleus, and it is there–not in the cytoplasm–that BIN2 meets up with BES1 and prevents it from activating growth genes. “All of a sudden the ‘BES1 shuttle model’ no longer made sense,” says Vert, adding that it took many carefully designed experiments to convince himself and others that it was time to retire the old model.

A new picture of how brassinosteroids stimulate plant growth now emerges based on those experiments: steroid hormones are still thought to inactivate BIN2 and reciprocally activate BES1, but instead of freeing BES1 to shuttle into the nucleus, it is now clear that the crucial activation step occurs in the nucleus where BES1 is already poised for action. Once released from BIN2 inhibition, BES1 associates with itself and other regulatory factors, and this modified form of BES1 binds to DNA, activating scores of target genes.

Referring to the work of Vert and other members of the brassinosteroid team, Chory says, “The old model may be out, but Greg’s new studies, together with those of former postdocs, Yanhai Yin and Zhiyong Wang, have allowed us to unravel the nuclear events controlling brassinosteroid responses at the genomic level. This turns our attention to the last mystery: the gap in our understanding of the events between steroid binding at the cell surface and these nuclear mechanisms.”

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Article adapted by MD Sports Weblog from original press release.
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Contact: Gina Kirchweger
Salk Institute

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

A team of researchers, led by scientists at Dartmouth Medical School and Dartmouth College, have identified and tested a gene that dramatically alters both muscle metabolism and performance. The researchers say that this finding could someday lead to treatment for muscle diseases, including helping the elderly who suffer from muscle deterioration and improving muscle performance in endurance athletes.

The researchers report that the enzyme called AMP-activated protein kinase (or AMPK) is directly involved in optimizing muscle activity. The team bred a mouse that genetically expressed AMPK in an activated state. Like a trained athlete, this mouse enjoyed increased capacity to exercise, manifested by its ability to run three times longer than a normal mouse before exhaustion.

One particularly striking feature of the finding was the accumulation of muscle glycogen, the stored form of carbohydrates, a condition that many athletes seek by “carbo-loading” before an event or game. The study appears in the Nov. 14 online issue of the American Journal of Physiology: Endocrinology and Metabolism.

“Our genetically altered mouse appears to have already been an exercise program,” says Lee Witters, the Eugene W. Leonard 1921 Professor of Medicine and Biochemistry at Dartmouth Medical School and professor of biological sciences at Dartmouth College. “In other words, without a prior exercise regimen, the mouse developed many of the muscle features that would only be observed after a period of exercise training.”

Witters, whose lab led the study, explains that this finding has implication for anyone with a muscle disease and especially for the growing proportion of the population that is aging. Deteriorating muscles often make the elderly much more prone to fall, leading to hip and other fractures. According to Witters, there is tremendous interest in the geriatric field to find ways to improve muscle performance.

“We now wonder if it’s possible to achieve elements of muscular fitness without having to exercise, which in turn, raises many questions about possible modes of exercise performance enhancement, including the development of drugs that could do the same thing as we have done genetically,” he says. “This also might raise to some the specter of ‘gene doping,’ something seriously being talked about in the future of high-performance athletes.”

Witters says that the carbohydrate, glucose, is a major fuel that powers muscles, and this contributes directly to a muscle’s ability to repetitively contract during exercise. The activated AMPK in the Dartmouth mouse appears to have increased glycogen content by actually switching on a gene that normally synthesizes liver glycogen.

“The switching on of this liver gene in muscles,” he says, “is a shift in the conception of the biochemistry of muscle metabolism, since many enzyme genes are thought to only be active in just one tissue.”

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Article adapted by MD Sports Weblog from original press release.
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Contact: Sue Knapp
Dartmouth College

Other authors on the paper include Laura Barré, Christine Richardson, and Steven Fiering, all at Dartmouth; Michael Hirshman and Laurie Goodyear of Joslin Diabetes Center in Boston; Joseph Brozinick with Eli Lilly and Company; and Bruce Kemp of the St. Vincent’s Institute in Australia.

This research is funded by the National Institutes of Health.

Steroid use by a Major League Baseball slugger may produce only modest increases in muscle mass and bat and ball speed but still boost home run production by 50 percent or more, according to a new study by Tufts University physicist Roger Tobin.

Tobin, a specialist in condensed matter physics with a long-time interest in the physics of baseball, will publish his paper “On the potential of a chemical Bonds: Possible effects of steroids on home run production in baseball” in an upcoming issue of the American Journal of Physics.

As Tobin’s paper notes, Babe Ruth’s record of 60 home runs in a single season stood for 34 years until Roger Maris hit 61 homers in 1961. For the next 35 years, no player hit more than 52 home runs in one season. But between 1998 and 2006, players hit more than 60 home runs in a season six times. Barry Bonds hit 73 home runs in 2001 — topping Maris’ mark by an astonishing 20 percent.

According to Tobin, the explosion in home runs coincides with the dawn of the “steroid era” in sports in the mid-1990s, and that surge quickly dropped to historic levels in 2003, when Major League Baseball instituted steroid testing.

While the increase in home runs has been clouded by suspected use of performance-enhancing steroids, many have wondered why home-running hitting would be particularly vulnerable to performance enhancement. They have also asked if it is even physically and physiologically plausible that steroids could produce effects of the magnitude observed. The answer to both questions, says Tobin, is “yes.”

Home Runs Disproportionately Affected

“A change of only a few percent in the average speed of the batted ball, which can reasonably be expected from steroid use, is enough to increase home run production by at least 50 percent,” he says. This disproportionate effect arises because home runs are relatively rare events that occur on the “tail of the range distribution” of batted balls.

“In most any statistical distribution — of people’s heights, SAT scores, or how far baseballs are hit — there’s a large bump where most of the values fall, with the graph falling rapidly as you move away from that region in either direction toward the rarer values,” explains Tobin. “It’s a well-known statistical property of such distributions that a relatively small shift in the center point of the distribution can produce a much larger proportional change in the number of values well above or below the center. Because the distribution’s ‘tail’ is particularly sensitive to small changes in the peak and/or width, home run records can be more strongly affected by steroid use than other athletic accomplishments.”

Muscle Mass Boosts Bat and Ball Speed

Tobin reviewed previous studies of the effect of steroid use and concluded that muscle mass, the force exerted by those muscles and the kinetic energy of the bat could each be increased by about 10 percent through the use of steroids. According to his calculations, the speed of the bat as it strikes the pitched ball will be about 5 percent higher than without the use of steroids and the speed of the ball as it leaves the bat will be about 4 percent higher.

To determine the ultimate impact on home run production, Tobin then analyzed a variety of models for trajectory of the baseball, accounting for gravity, air resistance and lift force due to the ball’s spin. While there was considerable variation among the models, “the salient point,” he says, “is that a 4 percent increase in ball speed, which can reasonably be expected from steroid use, can increase home run production by anywhere from 50 percent to 100 percent.”

What About the Pitchers?

Tobin applied a similar, though less extensive, mechanical analysis to pitching and found that smaller impacts were possible. He calculated that a 10 percent increase in muscle mass should increase the speed of a thrown ball by about 5 percent, or four to five miles per hours for a pitcher with a 90 mile per hour fastball. That translates to a reduction in earned run average of about 0.5 runs per game.

“That is enough to have a meaningful effect on the success of a pitcher, but it is not nearly as dramatic as the effects on home run production,” says Tobin. “The unusual sensitivity of home run production to bat speed results in much more dramatic effects, and focuses attention disproportionately on the hitters.”

A Reasonable Suspicion

Tobin is quick to acknowledge that athletes in many sports today achieve at a higher level than athletes of the past, and that this trend is not evidence of cheating. He also points out that many other changes, including adjustments in ballpark dimensions, league expansions, entry of African-American athletes, and lowering of the pitcher’s mound, could affect major league batting — although he says that none of those changes coincide with the sudden burst of home run production in the mid-1990s.

“Physics cannot tell us whether a particular home run was steroid-assisted, or even whether an extraordinary individual performance indicates the use of illicit means,” says Tobin.

But analysis of the physics, combined with physiology, yields telling results. “These results certainly do not prove that recent performances are tainted, but they suggest that some suspicion is reasonable,” he concludes.

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Article adapted by MD Sports Weblog from original press release.
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Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville, and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university’s schools is widely encouraged.

Source: Kim Thurler
Tufts University

A stunning discovery by German scientists may make blood doping and the treatment of severe anemia as easy as washing your hair.  

In the October print issue of The FASEB Journal (http://www.fasebj.org/), researchers show that the estimated 100,000 hair follicles on each person’s head have the potential to become erythropoietin (EPO) factories. EPO, the hormone primarily responsible for the creation of red blood cells, is used illegally to enhance athletic performance and is used legally to treat severe anemia associated with kidney failure and chemotherapy.

“The ultimate hope is that we’ll be able to up the production of natural EPO in our hair follicles whenever we need it, safely and at a low cost,” said Ralf Paus, senior author of the study. “Our study also highlights that ancient hormones are engaged in many more activities than conventional medical wisdom has assigned to them.”

Normally, EPO is created and released by the kidneys. When the kidneys fail, or when someone undergoes chemotherapy, this process is disrupted and severe anemia occurs. Today, most people are treated using synthetic EPO to bring red blood cells back to normal levels, but synthetic versions of this hormone are relatively expensive. Blood-doping athletes use synthetic EPO to help their bodies bring red blood cells to above-normal levels. This increased concentration of red blood cells allows the blood to deliver more oxygen to muscles than normal, significantly improving endurance and performance. The major danger in boosting the number of red blood cells above normal is that as the blood thickens with red blood cells, the possibility of heart attack increases.

“This study opens doors to an entirely new approach for treating EPO-related anemia,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “The study also is important because it suggests that there is still much to learn about ‘well known’ processes in the body.”

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Article adapted by MD Sports Weblog from original press release.
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Source: Cody Mooneyhan
Federation of American Societies for Experimental Biology

The FASEB Journal (http://www.fasebj.org/) is published by the Federation of American Societies for Experimental Biology (FASEB) and is consistently ranked among the top three biology journals worldwide by the Institute for Scientific Information. FASEB comprises 21 nonprofit societies with more than 80,000 members, making it the largest coalition of biomedical research associations in the United States. FASEB advances biological science through collaborative advocacy for research policies that promote scientific progress and education and lead to improvements in human health.

Steroid use starts early, decreases as teens grow older

Participation in sports with real or perceived weight requirements, such as ballet, gymnastics, and wrestling, is strongly associated with unhealthy weight control behaviors and steroid use in teens, according to researchers at the University of Minnesota.

Research published in the March 2007 issue of the Journal of the American Dietetic Association found nearly 6 percent of males between the ages of 12 and 18 who participated in weight-related sports induced vomiting within the week prior to being surveyed, as compared to only 0.9 percent of males who did not participate in weight- related sports. The use of diuretics within the previous year was reported by 4.2 percent of males in a weight-related sport, as opposed to 0.8 percent who did not participate in a weight-related sport.

Steroid use was reported in 6.8 percent of females who reported participating in weight-related sports, compared to 2.3 percent of those that weren’t active in a weight-related sport. Vomiting and using laxatives were also more likely in girls who were active in weight-related sports.

“The link between unhealthy weight-control behaviors and weight-related sports, especially in boys, is alarming,” said Marla Eisenberg, Sc.D., M.P.H., assistant professor at the University of Minnesota Medical School Department of Pediatrics. “Parents and coaches should emphasize skill and talent instead of weight and body image and educate teens about the negative health effects of steroid use and extreme weight control.” Researchers surveyed over 4,500 middle and high school students from the Minneapolis/St. Paul metro area. The students were asked if they had engaged in self-induced vomiting, used diet pills or laxatives, or used steroids within the previous week and year.

Steroid use in teens peaks at young age, but overall use has not increasedIn a separate study, published in the March 2007 issue of Pediatrics, University of Minnesota researchers surveyed the same teen population again five years later. They found that steroid use among teens peaked at 5 percent in middle school boys and girls, but as they grew older, steroid use declined significantly.

“It is encouraging to see that the majority of young people who reported using steroids in 1999 stopped using them as they got older,” said Patricia van den Berg, Ph.D., lead author of the study from the University of Minnesota School of Public Health. “But even given this decline, between one and three in 100 teens still reported using steroids within the last year when asked again 5 years later.”

Researchers conducted the longitudinal study with more than 2,000 adolescents to examine changes in eating patterns, weight, physical activity, and related factors over five years. Participants completed two surveys, one in 1999 and one in 2004, to determine if there were changes in steroid use.

Overall, 1.7 percent of boys and 1.4 percent of girls between the ages of 15 and 23 reported steroid use in 2004. Those that reported use early on were 4 to 10 times more likely to use later in life.

Boys who reported wanting a larger body in 1999, as well as those who said they used healthy weight-control behaviors, were more likely to take steroids when they were older. In contrast, girls who were heavier, less satisfied with their weight, and who had limited knowledge of healthy eating and exercise habits were more likely to take steroids as they grew older.

The study found no significant change in steroid use overall among teens from 1999-2004. “Our research suggests that the increased media coverage surrounding steroid use among athletes in recent years hasn’t led to a huge rise in steroid use in young people,” said van den Berg.

Anabolic-androgenic steroids are synthetic derivatives of the male hormone, testosterone. They are typically taken to increase muscle mass and strength for either improved sports performance or enhanced appearance. These steroids have significant negative effects on the body’s muscles, bones, heart, reproductive system, liver, and psychological state.

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Article adapted by MD Sports Weblog from original press release.
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Contact: Liz Wulderk
University of Minnesota 
 

Project EAT: Eating Among Teens Both studies are part of Project EAT: Eating Among Teens, research designed to investigate the factors influencing the eating habits of adolescents, to determine if youth are meeting national dietary recommendations, and to explore dieting, physical activity patterns, and related factors among youth. The project is designed to build a greater understanding of the socio-environmental, personal, and behavioral factors associated with diet and weight-related behaviors during adolescence so more effective nutrition interventions can be developed.

The studies were supported by the Maternal and Child Health Program, Health Resources and Services Administration, the Department of Health and Human Services, and a training grant from the Centers for Disease Control.