ERRγ as a Target for the Development of Exercise Mimetics

The research noted here is a representative example of efforts to reverse engineer the mechanisms by which exercise produces benefits, with an eye to achieving the same result with pharmaceutical compounds rather than exertion. Exercise works to grow muscle, improve endurance, and maintain long-term cardiovascular health through some set of mechanisms, as yet far from fully explored. The future of efforts to develop exercise mimetic drugs will no doubt be as laborious and difficult as the past fifteen years of work on calorie restriction mimetics, and for all the same reasons. Both are enormously broad and complex swathe of cellular biochemistry, poorly mapped, and expensive to explore.

In this area of research, even incremental advances in understanding have required years and a great deal of funding to achieve - just look at ongoing work on sirtuins, for example. As yet none of these programs have delivered meaningful approaches to therapy, treatments that might capture a sizable fraction of the effects of either exercise or calorie restriction. This will all change at some point, as biotechnology becomes ever more capable, but it seems foolish to imagine that it will happen in the next few years, given the past record. Even when it does, "so what?" we might ask. Exercise and calorie restriction cannot add decades to healthy life spans. We need a different approach to produce far longer healthy life.

If you've ever wondered how strenuous exercise translates into better endurance, researchers may have your answer. "ERRγ helps make endurance exercise possible. It gears up the energy-creating cellular power plants known as mitochondria, creating more blood vessels to bring in oxygen, take away toxins, and help repair damage associated with muscle use. This makes ERRγ a really interesting potential therapeutic target for conditions with weakened muscles."

The story starts with the PGC1α and PGC1β proteins, which stimulate 20 other proteins associated with skeletal muscle energy and endurance exercise, including ERRγ. In turn, ERRγ, a hormone receptor, acts to turn on genes. Researchers wanted to precisely understand ERRγ's role in skeletal muscle energy production and how that impacts physical endurance. To unravel this relationship, the team studied mice without PGC1α/β. In some, they increased ERRγ selectively in skeletal muscle cells. This approach allowed them to measure how ERRγ and PGC1 act independently, as well as how they function in combination.

Losing PGC1 had a negative impact on muscle energy and endurance. However, boosting ERRγ restored function. The team found ERRγ is essential to energy production, activating genes that create more mitochondria. In other words, they found the power switch for skeletal muscles. The researchers also showed that increased ERRγ in PGC1-deficient mice boosted their exercise performance. By measuring voluntary wheel running, they found that increasing ERRγ produced a five-fold increase in time spent exercising compared to mice with no PGC1 and normal ERRγ levels. "Now that we have detected this direct target (ERRγ) for exercise-induced changes, we could potentially activate ERRγ and create the same changes that are being induced by exercise training."



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