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.