Towards an exercise pill for humans with a drug that boosts muscle and running endurance by 50%

The drug candidate, SR9009, is one of a pair of compounds developed in the laboratory of TSRI (The Scripps Research Institute) Professor Thomas Burris which reduced 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.

If this can works in human it will anble new therapies for obesity, metabolic syndrome and diabetes. It could also help people with severe arthritis, congestive heart failure, chronic obstructive pulmonary disease (COPD), and other conditions that restrict the ability to exercise.

(a) Western blot analysis of Rev-erb-α protein levels in mouse muscles; actin was used as control. Qua, quadriceps; Sol, soleus; Gas, gastrocnemius; EDL, extensor digitorum longus; Dia, diaphragm; TA, tibialis anterior

Nature Medicine – Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy

ABSTRACT
The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1–Ppargc-1α signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In complementary experiments, Rev-erb-α overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-α in vivo increased exercise capacity. This study identifies Rev-erb-α as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.

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