These findings could lead to new approaches to helping people with conditions that acutely limit exercise tolerance, such as obesity, chronic obstructive pulmonary disease (COPD) and congestive heart failure, as well as the decline of muscle capacity associated with aging.
The study was published July 14, 2013, by the journal Nature Medicine.
The drug candidate, SR9009, is one of a pair of compounds developed in the laboratory of TSRI Professor Thomas Burris and described in a March 2012 issue of the journal Nature as reducing obesity in animal models. The compounds affect the core biological clock, which synchronizes the rhythm of the body’s activity with the 24-hour cycle of day and night.
The compounds work by binding to one of the body’s natural molecules called Rev-erbα, which influences lipid and glucose metabolism in the liver, the production of fat-storing cells and the response of macrophages (cells that remove dying or dead cells) during inflammation.
In the new study, a team led by scientists at the Institut Pasteur de Lille in France demonstrated that mice lacking Rev-erbα had decreased skeletal muscle metabolic activity and running capacity. Burris’ group showed that activation of Rev-erbα with SR9009 led to increased metabolic activity in skeletal muscle in both culture and in mice. The treated mice had a 50 percent increase in running capacity, measured by both time and distance.
“The animals actually get muscles like an athlete who has been training,” said Burris. “The pattern of gene expression after treatment with SR9009 is that of an oxidative-type muscle— again, just like an athlete.”
The authors of the new study suggest that Rev-erbα affects muscle cells by promoting both the creation of new mitochondria (often referred to as the “power plants” of the cell) and the clearance of those mitochondria that are defective.
The study, “Rev-Erbα Modulates Skeletal Muscle Oxidative Capacity by Regulating Mitochondrial Biogenesis and Autophagy” was led by Estelle Woldt and Yasmine Sebti (first authors) and Bart Staels and Hélène Duez (senior authors) of Institut Pasteur de Lille, France. Other contributors include Christian Duhem, Jérôme Eeckhoute, Charlotte Paquet, Stéphane Delhaye and Philippe Lefebvre of Institut Pasteur de Lille, France; Laura Solt, Youseung Shin, Thomas Burris and Theodore M. Kamenecka of TSRI; Steve Lancel and Rémi Nevière of Université Lille Nord de France; and Matthijs K.C. Hesselink, Gert Schaart and Patrick Schrauwen of Maastricht University Medical Center, Maastricht, the Netherlands.
The study was supported by a Marie Curie International Reintegration Grant (FP7), the European Commission (FP7) consortium Eurhythdia, Région Nord Pas-de-Calais/FEDER, a CPER “starting grant,” the European Genomic Institute for Diabetes (ANR-10-LABX-46), an unrestricted ITMO/Astra Zeneca grant, a joint Société Francophone du Diabète MSD research fellowship, Research Grant from the European Foundation for the Study of Diabetes, National Institutes of Health grant (MH093429 and DK080201) and a VICI Research grant for innovative research from the Netherlands Organization for Scientific Research (918.96.618).
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
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