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Molecule linked to muscle fatigue in humans; enhances exercise tolerance when fed to mice

Cell Press

Everyone's muscles have different limits. While professional athletes can train for hours before feeling fatigued, others struggle to mow the lawn or climb stairs. No panacea exists to create an equal playing field, nor will one likely be discovered, but a new study from Duke University questions whether this limit can be nutritionally extended. The research appears July 7 in Cell Metabolism as part of a special issue on "Physical Activity and Metabolic Health."

The researchers began by identifying an enzyme in skeletal muscle that helps to enhance how much moderate or vigorous work a person can tolerate. Muscle cells get their strength from their above-average numbers of mitochondria, the so-called cellular powerhouses. Chemical reactions that take place within these organelles use nutrient-derived metabolites to produce energy-rich molecules called ATP and phosphocreatine, which other parts of the cell use to function. An enzyme that generates some of these mitochondrial metabolites, called carnitine acetyltransferase (CrAT), has been known of for many years, but how it contributed to exercise was undefined.

"To address this gap we engineered mice that lack the gene encoding CrAT, specifically in skeletal muscle, and evaluated their ability to perform exercise," says senior study author Deborah Muoio, a metabolic physiologist at the Duke Molecular Physiology Institute. "The CrAT-deficient mice were compared against a control group of genetically identical mice, with the exception of the CrAT gene, which was present and normally active in the controls. We found that the mice lacking CrAT fatigued earlier during various types of exercise tolerance tests because their muscles had more difficulty meeting the energy demands of the activity."

The researchers next looked at the relationship between CrAT levels and the ability of human muscles to make energy. To do this, Muoio and her lab--including co-lead authors Sarah Seiler and Timothy Koves--collaborated with a team at Maastricht University in the Netherlands who recently developed a non-invasive method for measuring CrAT activity in human muscle. Using this method, they observed that CrAT activity increases with exercise training but decreases in association with aging and age-related metabolic diseases, such as type 2 diabetes.

These combined results led Muoio to question whether the CrAT metabolite could be therapeutically manipulated to have a positive effect on physical activity, such as by allowing an individual to exercise for longer. One potential candidate to increase CrAT metabolite activity is a micronutrient it uses called carnitine.

"Although our body makes carnitine, the amount produced declines with age and in certain disease states, implying that supplements might be beneficial in some cases," Muoio says. "In further animal studies we found that carnitine supplementation improved exercise tolerance, but only in the control group with normal CrAT activity in muscle. The results strongly imply that carnitine and the CrAT enzyme work together to optimize muscle energy metabolism during exercise."

Surprisingly, carnitine supplementation increased exercise stamina in healthy, young adult mice. It is not known whether carnitine can have the same benefits in humans, and the biology behind how CrAT activity improves muscle energy use is still unfolding. Muoio believes that CrAT works to help muscle function by adjusting mitochondrial output when muscles transition from a lower to higher work rate, and vice versa. Her lab is in the process of conducting additional animal studies as this work has promise to lead to clinical trials in humans.

"Our priority in the near term is to determine if carnitine supplementation augments the benefits of exercise training in older individuals at risk of metabolic disease," she says. However, Muoio cautions: "The work is not meant to imply that everyone should be taking carnitine supplements. We need to move beyond the "one size fits all" approach to optimal nutrition and instead work toward more personalized prescriptions that consider underlying genetics and acquired conditions."


The work was primarily supported by the United States Public Health Service and the American Heart Association.

Cell Metabolism, Seiler and Koves et al.: "Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue During Exercise"

Cell Metabolism, published by Cell Press, is a monthly journal that publishes reports of novel results in metabolic biology, from molecular and cellular biology to translational studies. The journal aims to highlight work addressing the molecular mechanisms underlying physiology and homeostasis in health and disease. For more information, please visit To receive media alerts for Cell Metabolism or other Cell Press journals, contact

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