The candy bar you swallowed right before jumping on your bicycle keeps you going only so long before the muscles in your legs and hips reach for something with more power – the long chain fatty acids stored to keep you moving for hours.
In a report in the journal Cell Metabolism, Dr. Bert O'Malley, professor and chair of molecular and cellular biology at Baylor College of Medicine, Dr. Brian York, assistant professor in the same department, and colleagues at BCM describe how a coactivator called steroid receptor-3 (SRC-3) controls the metabolism of these long chain fatty acids in skeletal muscle by regulating the expression of a gene for the enzyme carnitine/acyl-carnitine translocase (CACT). (A coactivator is a protein that increases the expression of a gene by binding to an activator or a transcription factor. Coactivators cannot bind directly to DNA.)
The finding incorporates the use of metabolomics into laboratory studies using animals and knowledge of human disease to link SRC-3 to this skeletal muscle disorder.
O'Malley and his colleagues performed a metabolomic-based analysis to find out how loss of SRC-3 affects metabolism in tissues and in various metabolic pathways. The analysis showed that the metabolic signature of SRC-3 specifically affected skeletal muscle. (Metabolomics refers to a global analysis similar to a genomic sequence, but in this case, it details the small molecules generated by metabolism.)
In studies of mice in which SRC-3 has been removed, the researchers found the animals to be weak, have low sugar and ketones in the blood, too much ammonia, heart arrhythmias and seizures. All these can be symptoms of people who lack the CACT gene. However, the mice only lack SRC-3 – not CACT.
"If you cannot get the long chain fatty acids into the mitochondria (the powerhouses of the cell), then they cannot be metabolized and used for energy. The enzyme associated with CACT takes the long chain fatty acids into the mitochondria," O'Malley said.
Overfeeding the mice (and the people who lack the CACT gene) with foods that contain short chain fatty acids can help overcome the problem, he said.
"That's what we do for people with this disorder," he said. "We often use an artificial food that contains these short chain fatty acids that they eat along with a normal diet."
"This is the first time we have linked SRC-3 to muscle," he said. SRC-3 is a master regulator of cellular activities. In previous studies, O'Malley and his colleagues have linked its overexpression to cancer.
"This is a disease of underexpression," said O'Malley.
Coactivators can make biggest difference The finding takes the understanding of the links between genes and disease to a new level.
"If you get a genetic disease, you think there is something wrong with the DNA. If you have a transcription factor (that affects how the DNA is translated into the RNA template for a protein) that activates the gene and there is a problem, there you have a disease too. But that transcription factor recruits a coactivator (like SRC-3), and if there is a defect in the coactivator, it can predispose you to disease that might show up over the lifetime. It might not be as blatant or as obvious, but it is still there. Coactivators can make the biggest difference on the expression of genes," said O'Malley.
Others who took part in this work include Erin L. Reineke, Bryan C. Nikolai, Suoling Zhou, Jean-Francois Louet, Atul R. Chopra, Xian Chen, Graham Reed, Jeffrey Noebels, Adekunle M. Adesina, Hui Yu, Lee-Jun C. Wong, Anna Tsimelzon, Susan Hilsenbeck and Jianming Xu, all of BCM; Jørn V. Sagen of the University of Bergen in Norway, and Robert D. Stevens, Brett R. Wenner, Olga Ilkayeva, Christopher B. Newgard, all of Duke University Medical School in Durham, N.C.
Funding for this work came from the Nuclear Receptor Signaling Atlas of the National Institute of Diabetes and Digestive and Kidney Diseases, the NIDDK-funded Diabetes and Endocrinology Research Center at BCM, the Norwegian Cancer Society, the Norwegian Society of Endocrinology, The Western Norway Regional Health Authority and the National Institutes of Health.