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.
Action Points
- The nuclear receptor Rev-erb-alpha is highly expressed in oxidative skeletal muscle, and deficiency in muscle in mice leads to reduced mitochondrial content and oxidative function, and leads to compromised exercise capacity.
- In addition, Rev-erb-alpha muscle overexpression, as well as pharmacological activation of Rev-erb-alpha in vivo, increased exercise capacity.
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.
