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## Endocrinology

# Compound Keeps Muscles from Clocking Out

Published: Jul 18, 2013

By Crystal Phend, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
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Stimulating a circadian clock component can "wake up" muscle metabolic function and boost exercise endurance, an animal study showed.

A compound to boost expression of the nuclear receptor Rev-erb-alpha increased metabolic activity in skeletal muscle and made mice able to run 50% longer and further, Hélène Duez, PhD, of the Institut Pasteur de Lille, France, and colleagues found.

"Thus, pharmacological activation of Rev-erb-alpha may be a promising approach for the treatment of skeletal muscle diseases with compromised exercise capacity," the group wrote online in Nature Medicine.

Good candidates might include chronic obstructive pulmonary disease, congestive heart failure, and even obesity.

Rev-erb-alpha is a component of the circadian clock that modulates hepatic lipid and glucose metabolism, fat cell development, and the inflammatory response in macrophages. The researchers looked for a role in skeletal muscle, which also has a circadian rhythm to gene expression.

They found that Rev-erb-alpha expression was much higher in the slow oxidative muscle fibers that are resistant to fatigue than in the fast glycolytic muscles that contract and tire quickly.

Mice bred for low Rev-erb-alpha expression were observed to move around less than their wild-type littermates, and to have 60% lower exercise capacity in a forced treadmill test. Skeletal muscle samples showed 40% less mitochondrial DNA and reduced mitochondrial oxidative capacity in the low Rev-erb-alpha mice.

Other experiments showed that Rev-erb-alpha regulates muscle cell mitochondrial function and biogenesis as well, while a deficiency in it reduces the number of mitochondria by inducing the self-digestion process of autophagy that clears out damaged cell parts.

Rev-erb-a deficiency deactivated the Lkb1-Ampk-Sirt1–Ppargc-1a signaling pathway, components of which allow skeletal muscle to switch fuel sources during fasting and exercise and play roles in mitochondrial respiration and function.

"Together, these data support the concept that Rev-erb-alpha acts through a two-pronged mechanism, involving both biogenesis of new mitochondria and clearance of defective mitochondria," the researchers explained.

The group also showed that while deficiency hurt muscle functional capacity, extra Rev-erb-alpha helped it.

Mice treated with a synthetic ligand dubbed SR9009, which had previously been used in reducing obesity in an animal model, showed a significant increase in mitochondrial function and exercise capacity.

Running capacity was 60 minutes compared with 40 minutes in untreated mice, while running distance came in at over 1,000 m with the compound versus less than 700 m without it (both P<0.05).

Cells treated in vitro with the compound showed an increase in the number of total and active mitochondria.

"Thus, when Rev-erb-alpha is activated, there is an increase in mitochondrial number and a better control of autophagic flux, allowing for a higher oxidative capacity," Duez's group noted.

The research was supported by a Marie Curie International Reintegration Grant, the European Commission consortium Eurhythdia, Région Nord Pas-de-Calais/Fonds Européen de Développement Régional, a Contrat de Projet Etat-Région 'starting grant', the European Genomic Institute for Diabetes, an unrestricted Instituts Thématiques Multi-Organismes/Astra Zeneca grant, a joint Société Francophone du Diabète/Merck Sharp & Dohme research fellowship, a research grant from the European Foundation for the Study of Diabetes/Lilly, National Institutes of Health grants, a National Research Service Award, and the Netherlands Organization for Scientific Research.

The researchers reported having no conflicts of interest to disclose.

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Primary source: Nature Medicine
Source reference:
Woldt E, et al "Rev-erb-alpha modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy" Nat Med 2013; DOI: 10.1038/nm.3213.

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Crystal Phend

Staff Writer

Follow @cphend
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Crystal Phend joined MedPage Today in 2006 after roaming conference halls for publications including The Medical Post, Oncology Times, Doctor's Guide, and the journal IDrugs. When not covering medical meetings, she writes from Silicon Valley, just south of the San Francisco fog.
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