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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Research News
Ingestion of Special Carbohydrates Improves Exercise Performamce Amino Acids that Tell Muscle Cells to Build Protien Carbohydrate Intake Supports Muscle Proteing Synthesis

Bethesda, MD – A visit to the meat counter at any supermarket is proof positive that a good number of Americans are avoiding carbohydrates and consuming high levels of protein and fat, in accordance with the Atkins diet. This carbohydrate-free, fat- and protein- rich diet is for those seeking immediate weight loss, which means most of us.But what do others, such as weight lifters and callisthenic enthusiasts, do about carbohydrates? Their goal is muscle preservation and strengthening, but for years, different theories have been offered about the effectiveness of carbohydrates in maintaining an appropriate muscle protein balance. A new study may lead to a truce in the debate at the nation’s gymnasiums, and those dedicated to resistance training may finally have an answer as to whether carbohydrates have a positive role in muscle development.

Background

Resistance exercise — also called strength training — increases muscle strength and mass, bone strength, and the body’s metabolism. The different methods for resistance training include free weights, weight machines, calisthenics and resistance tubing. When using free weights, dumbbells, and bars stacked with weight plates, you are responsible for both lifting the weight and determining and controlling your body position through the range of motion.

The body’s net muscle protein balance (i.e., the difference between muscle protein synthesis and protein breakdown) generally remains negative in the recovery period after resistance exercise in the absence of nutrient intake, i.e., the muscle’s protein is breaking down complex chemical compounds to simpler ones. However, it has been demonstrated that infusion or ingestion of amino acids after resistance exercise stimulates muscle protein synthesis. Furthermore, as little as six grams of essential amino acids (EAA) alone effectively stimulates net protein synthesis after a strenuous resistance exercise session.

The body’s response to the six grams of EAA does not appear to differ when 35 grams of carbohydrates are added. This reflects the uncertainty of the independent effects of carbohydrates on muscle protein metabolism after resistance exercise. Additionally, it is unclear how carbohydrate intake causes changes of net protein balance between synthesis and breakdown and how it relates to changes in plasma insulin concentration.

Interpretation of the response of muscle protein to insulin is complicated by the fact that a systemic increase in insulin concentration causes a fall in plasma amino acid concentrations, and this reduced amino acid availability could potentially counteract a direct effect of insulin on synthesis. A past study found that the normal postexercise increase in muscle protein breakdown was slowed by insulin, thus improving net muscle protein balance. However, whereas local infusion of insulin may effectively isolate the effect of insulin per se, the response may differ from when insulin release is stimulated by ingestion of carbohydrates.

A New Study

Accordingly, a new study set out to investigate the independent effect of carbohydrate intake on muscle protein net balance during recovery from resistance exercise. The authors of “Effect Of Carbohydrate Intake on Net Muscle Protein Synthesis During Recovery from Resistance Exercise,” are Elisabet Børsheim, Melanie G. Cree, Kevin D. Tipton, Tabatha A. Elliott, Asle Aarsland, and Robert R. Wolfe, all from the Department of Surgery, Metabolism Unit, Shriners Hospitals for Children-Galveston, University of Texas Medical Branch, Galveston, TX. Their findings appeared in the February 2004 edition of the Journal of Applied Physiology. The journal is one of 14 peer-reviewed scientific journals published each month by the American Physiological Society (www.APS.org).

Methodology

Sixteen recreationally active and healthy subjects took part in the study. At least one week before an experiment, subjects were familiarized with the exercise protocol, and their one repetition maximum, a maximum weight possible with a leg extension, was determined. The subjects were assigned to one of two groups: carbohydrate group (CHO; n = or placebo group (n = 8). Subjects were instructed not to exercise for at least 48 hours before an experiment, not to use tobacco or alcohol during the 24 h before an experiment, and not to make any changes in their dietary habits.

The two groups of eight subjects performed a resistance exercise bout (10 sets of eight repetitions of leg presses at 80 percent of one repetition maximum) before they rested in bed for four hours. One group (CHO) received a drink consisting of 100 grams of carbohydrates one hour after exercise; the placebo group received a noncaloric placebo drink. Leg amino acid metabolism was determined by infusion of 2H5- or 13C6-labeled phenylalanine, sampling from femoral artery and vein, and muscle biopsies from vastus lateralis, the lateral head of quadriceps muscle of anterior (extensor) compartment of thigh.

Results

Key findings of the study included: 

• Plasma glucose concentration was significantly increased in the carbohydrate group until 210 min after intake of drink. 
• Plasma concentration of insulin reflected the changes in glucose concentration. The drink intake did not affect arterial insulin concentration in the placebo group, whereas arterial insulin increased by several times after the drink in the CHO group. 
• Arterial phenylalanine (a common amino acid in proteins) concentration did not change after intake of drink in the placebo group but decreased and stabilized in the CHO group. 
• Net muscle protein balance between synthesis and breakdown did not change in the placebo group but improved in the CHO group during the second and third hour after the drink. The improved net balance in the CHO group was due primarily to a progressive decrease in muscle protein breakdown.

Conclusions

This study is the first to compare net muscle protein balance (protein synthesis minus breakdown) after carbohydrate ingestion with control after exercise. The principal finding was that intake of 100 grams of carbohydrates after resistance exercise improved muscle net protein balance.

The findings from this research demonstrate that carbohydrates intake alone can improve net protein balance between synthesis and breakdown. In this work, the gradual improvement in net muscle protein balance after carbohydrate intake was due principally to a progressive reduction in breakdown. However, the improvement was small compared with previous findings after intake of amino acids or amino acids and carbohydrates.

The researchers conclude that intake of carbohydrates alone after resistance exercise will modestly improve the anabolic effect of exercise. However, amino acid intake is necessary for a maximal response, one desired by most participating in resistance exercise programs.

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Article adapted by Sports Performance Research from original press release.

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Contact: Donna Krupa

American Physiological Society 

Source: Journal of Applied Physiology. The journal is one of 14 peer-reviewed scientific journals published each month by the American Physiological Society (www.APS.org).

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.