A new study finds that restricted nutrient availability prevents muscle stem cells from growing into mature muscle cells. The research, published by Cell Press in the May issue of the journal Developmental Cell, provides exciting new information about how developing muscle cells sense and respond to nutrient levels. The study adds a new twist to ongoing research into the effects of caloric restriction on physiology and aging and may lead to new therapeutic avenues for muscle wasting.

Although it is certainly rational to expect that access to nutrients, such as the simple sugar glucose, has a profound impact on the development of human cells, the cellular strategies for responding to fluctuations in nutrient availability are not well understood. Drs. Vittorio Sartorelli and Marcella Fulco from the National Institutes of Health investigated how the availability of glucose affects the ability of muscle stem cells, called myoblasts, to develop (or “differentiate”) into mature skeletal muscle fibers.

The researchers found that glucose restriction (GR) impaired differentiation of skeletal myoblasts and activated AMP-activated protein kinase (AMPK). These results define a pathway in which activation of AMPK in response to low glucose levels stimulates expression of the NAD+ biosynthetic enzyme Nampt. NAD+ is a known cofactor of SIRT1, which plays an important role in numerous physiological processes, including differentiation of skeletal muscle cells, and has been implicated in regulation of lifespan and aging. Importantly, inhibition of AMPK, Nampt or SIRT1 resulted in skeletal muscle cells that were oblivious to a nutrient poor environment and were able to differentiate under conditions that otherwise would not be suitable.

These results demonstrate that a defined pathway actively controls muscle differentiation in response to low nutrients. “We speculate that, functioning as a cellular checkpoint, the AMPK-Nampt-SIRT1 pathway may be activated by reduced nutrient availability to prevent cells from undertaking energy demanding processes – such as cell differentiation – during calorie-unfavorable conditions. On the other hand, once nutrients become available, the pathway is inactivated to allow resumption of physiological development,” offers Dr. Sartorelli.

The study has important implications that extend beyond muscle development. This mechanism also operates in adult tissues and thus would be part of the response to a dietary regimen that restricts caloric intake. Further, the researchers found that glucose restriction or treatment of skeletal muscle cells with metformin, a drug used to treat type II diabetes, had similar outcomes and resulted in the activation of SIRT1. “It is therefore possible that the well-known benefits that diabetics derive from lowering the calorie intake in their diet may be attributable to activation of the AMPK-Nampt-SIRT1 axis” comments Dr. Sartorelli. It is also attractive to speculate that AMPK and SIRT1 may prove to be rational targets for counteracting the devastating effects of muscle wasting.

The researchers include Marcella Fulco, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD; Yana Cen, Weill Medical College of Cornell University, New York, NY; Po Zhao, Children’s National Medical Center, Washington, DC; Eric P. Hoffman, Children’s National Medical Center, Washington, DC; Michael W. McBurney, Ottawa Health Research Center Institute, Ottawa, Canada; Anthony A. Sauve, Weill Medical College of Cornell University, New York, NY; and Vittorio Sartorelli, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.

Early indications show that nutritional supplements may lessen muscle atrophy brought on by space travel, prolonged bed confinement or immobility. To study space travel’s effect on muscles, Dr. Robert Wolfe of the University of Texas Medical Branch at Galveston enlisted healthy subjects to stay in bed 28 days during a National Space Biomedical Research Institute study.

“One cause of muscle atrophy in space is lack of muscular activity. That’s why bed rest is a good model because it minimizes activity, and like astronauts, you lose muscle mass primarily in the legs,” said co-investigator Dr. Arny Ferrando, a professor of surgery at UTMB and Shriners Hospital for Children in Galveston. “When muscles are inactive, as they are in space, they don’t make new proteins. If muscle breakdown rates are the same, that means you lose muscle.”

Researchers are attempting to increase protein synthesis rates with supplements of amino acids, which are the raw materials of protein. Participants received the supplements three times a day, and researchers compared the protein synthesis/breakdown rates and muscle mass before and after the bed-rest study. This data was compared to results from a control group that received a placebo drink instead of the supplements.

“Early results suggest that the amino acid supplement is able to maintain synthesis rates and body mass,” Ferrando said.

During the study, subjects must remain in bed and can get up only briefly to use a bedside commode. They eat and bathe from their beds, and daily activities encompass watching television, reading books and using a bedside computer.

Midway through the study, researchers determine muscle mass and function by testing the subjects’ strength and body composition.

They gather the most vital data, the protein synthesis and breakdown rates, by using stable isotope analysis. With the stable isotope technique, researchers attach a harmless tracer to specific amino acids that travel through the bloodstream. Then, they take blood samples to determine the amount of amino acids that enter and exit the leg.

“If 80 amino acids are coming into the artery and 60 are going out of the vein, we know that 20 were probably made into proteins in the muscle,” said Dr. Douglas Paddon-Jones, also of UTMB and a co-investigator performing these studies. “We complete the muscle analysis by removing a small piece of muscle and determining how many amino acids have been incorporated into proteins. Over time, we can calculate the rate at which the synthesis and breakdown occurs.”

Space conditions also elevate the body’s level of the stress hormone cortisol, which increases the breakdown rate of proteins. “Under stress, the body breaks down proteins to make energy for survival,” said Ferrando, a member of NSBRI’s nutrition and fitness research team. “However, this process also causes muscle atrophy.”

To study the supplement’s effects on muscle loss due to elevated levels of cortisol, researchers infused the stress hormone into the participants’ blood during the stable isotope tests. The researchers mimic the cortisol concentrations found during space flight, then determine protein synthesis and breakdown rates of the subjects taking the supplement and compare this to the rates of the control group.

Ferrando and Wolfe are also collaborating with other NSBRI researchers who use the subjects’ body fluids to study changes in bone, immune function and cell damage induced by bed rest.

Findings from this research on nutritional supplements could benefit patients on Earth.

“Muscle atrophy is common in many populations: the elderly, kids with burns, patients in intensive care or people who have had major operations. We’re looking at this phenomenon in terms of space flight, but the study has many other implications,” Ferrando said.

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Article adapted by MD Sports from original press release.
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Contact: Kathy Major
National Space Biomedical Research Institute 

The NSBRI’s consortium members include Baylor College of Medicine, Brookhaven National Laboratory, Harvard Medical School, The Johns Hopkins University, Massachusetts Institute of Technology, Morehouse School of Medicine, Mount Sinai School of Medicine, Rice University, Texas A&M University, University of Arkansas for Medical Sciences, University of Pennsylvania Health System and University of Washington.

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 In many HIV-infected individuals with prior weight loss, the failure to regain weight and lean tissue is at least in part the consequence of inadequate protein intake or ingestion of a poor-quality protein rather than total caloric intake. Dietary sources of protein are presumably inadequate to meet the high metabolic needs caused by HIV infection. To achieve a target protein intake in the range (1.5 to 2.0 g/kg/day) demonstrated in other catabolic diseases necessary to achieve positive nitrogen balance and to generate substantial anabolic effects.

A high-quality protein food supplement may help HIV-positive patients maintain, and possibly gain, muscle mass. Many HIV-positive patients lose weight that they are then unable to regain. This may be because patients are not eating enough protein or are not eating the right kinds of protein. The protein eaten in foods (such as meat, eggs, or beans) may not be able to make up for the amount of protein lost due to HIV infection.

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Negative Energy Balance

By Sandco Staff

University Park, Pa. - Female athletes often lose their menstrual cycle when training strenuously, but researchers have long speculated on whether this infertility was due to low body fat, low weight or exercise itself. Now, researchers have shown that the cause of athletic amenorrhea is more likely a negative energy balance caused by increasing exercise without increasing food intake.

“A growing proportion of women are susceptible to losing their menstrual cycle when exercising strenuously,” says Dr. Nancy I. Williams, assistant professor of kineseology and physiology at Penn State. “If women go six to 12 months without having a menstrual cycle, they could show bone loss. Bone densities in some long distance runners who have gone for a prolonged time period without having normal menstrual cycles can be very low.”

In studies done with monkeys, which show menstrual cyclicity much like women, researchers showed that low energy availability associated with strenuous exercise training plays an important role in causing exercise-induced amenorrhea. These researchers, working at the University of Pittsburgh, published findings in the Journal of Clinical Endocrinology and Metabolism showing that exercise-induced amenorrhea was reversible in the monkeys by increasing food intake while the monkeys still exercised.

Williams worked with Judy L. Cameron, associate professor of psychiatry and cell biology and physiology at the University of Pittsburgh. Dana L. Helmreich and David B. Parfitt, then graduate students, and Anne Caston-Balderrama, at that time a post-doctoral fellow at the University of Pittsburgh, were also part of the research team. The researchers decided to look at an animal model to understand the causes of exercise-induced amenorrhea because it is difficult to closely control factors, such as eating habits and exercise, when studying humans. They chose cynomolgus monkeys because, like humans, they have a menstrual cycle of 28 days, ovulate in mid-cycle and show monthly periods of menses.

“It is difficult to obtain rigorous control in human studies, short of locking people up,” says Williams.

Previous cross-sectional studies and short-term studies in humans had shown a correlation between changes in energy availability and changes in the menstrual cycle, but those studies were not definitive.

There was also some indication that metabolic states experienced by strenuously exercising women were similar to those in chronically calorie restricted people. However, whether the increased energy utilization which occurs with exercise or some other effect of exercise caused exercise-induced reproductive dysfunction was unknown.

“The idea that exercise or something about exercise is harmful to females was not definitively ruled out,” says Williams. “That exercise itself is harmful would be a dangerous message to put out there. We needed to look at what it was about exercise that caused amenorrhea, what it was that suppresses ovulation. To do that, we needed a carefully controlled study.”

After the researchers monitored normal menstrual cycles in eight monkeys for a few months, they trained the monkeys to run on treadmills, slowly increasing their daily training schedule to about six miles per day. Throughout the training period the amount of food provided remained the standard amount for a normal 4.5 to 7.5 pound monkey, although the researchers note that some monkeys did not finish all of their food all of the time.

The researchers found that during the study “there were no significant changes in body weight or caloric intake over the course of training and the development of amenorrhea.” While body weight did not change, there were indications of an adaptation in energy expenditure. That is, the monkeys’ metabolic hormones also changed, with a 20 percent drop in circulating thyroid hormone, suggesting that the suppression of ovulation is more closely related to negative energy balance than to a decrease in body weight.

To seal the conclusion that a negative energy balance was the key to exercise-induced amenorrhea, the researchers took four of the previous eight monkeys and, while keeping them on the same exercise program, provided them with more food than they were used to. All the monkeys eventually resumed normal menstrual cycles. However, those monkeys who increased their food consumption most rapidly and consumed the most additional food, resumed ovulation within as little as 12 to 16 days while those who increased their caloric intake more slowly, took almost two months to resume ovulation.

Williams is now conducting studies on women who agree to exercise and eat according to a prescribed regimen for four to six months. She is concerned because recreational exercisers have the first signs of ovulatory suppression and may easily be thrust into amenorrhea if energy availability declines. Many women that exercise also restrict their calories, consciously or unconsciously.

“Our goal is to test whether practical guidelines can be developed regarding the optimal balance between calories of food taken in and calories expended through exercise in order to maintain ovulation and regular menstrual cycles,” says Williams. “This would then ensure that estrogen levels were also maintained at healthy levels. This is important because estrogen is a key hormone in the body for many physiological systems, influencing bone strength and cardiovascular health, not just reproduction.”

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Article adapted by MD Sports from original press release.
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Contact: A’ndrea Elyse Messer
Penn State

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Nitrogen Balance

By Sandco Staff