Muscle stem cells, or myoblasts, play an important role in the maintenance and repair of muscle tissue, but the factors regulating their differentiation into mature muscle fibres are not fully understood. Now, new research published in the May issue of Developmental Cell demonstrates that glucose restriction prevents myoblasts from differentiating1. The paper also maps out the biochemical pathway that allows the cells to sense and adapt to nutrient availability in their environment, which may lead to new therapeutic targets for muscle-wasting diseases. Furthermore, by exposing a new mechanism by which cells respond to fluctuations in nutrient availability, this work is adding to the understanding of the effects of caloric restriction on mammalian physiology.

The study was led by Vittorio Sartorelli, a researcher at the National Institute of Arthritis, Musculoskeletal and Skin Diseases, in Bethesda, Maryland, whose lab is investigating the mechanisms involved in the proliferation and differentiation of skeletal muscle cells. The work implicates AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) — two molecules that are important mediators of cellular metabolism — in myogenesis. The authors had previously shown that SIRT1, which is part of an evolutionarily conserved family of enzymes called deacetylases, is a negative regulator of muscle development; however, the mechanism was not well understood2. SIRT1 also plays a role in numerous other physiological processes, including stress resistance and aging (SIRT1's yeast homolog, the Sir2 protein, dramatically extends the organism's lifespan under conditions mimicking caloric restriction).

In the Developmental Cell paper, Sartorelli's team shows that AMPK is activated in both mouse myoblasts and C2C12 cells (also from mice) when glucose concentration in cell culture medium is low — the first time APMK has been directly shown to be involved in myogenesis. AMPK activation causes an increase in the intracellular NAD+/NADH ratio, which is then sensed by the NAD+-dependent histone deacetylase SIRT1. Therefore, SIRT1 appears to be the vehicle through which AMPK blocks muscle cell differentiation. Inhibition of AMPK or SIRT1 — with pharmacological agents, RNA interference or gene knockouts — rendered skeletal muscle cells oblivious to the nutrient-poor environment, and so they differentiated normally.

Although there is still much work to be done in muscle, for example in determining whether AMPK and SIRT1 activity is important for muscle development in vivo, the work has implications for other tissues as well. The authors speculate that this molecular pathway “may be part of a functionally coherent strategy developed by the cell to cope with reduced nutrient availability.” In other words, when nutrients are in low supply, the pathway is activated and prevents cells from undertaking energy-intensive processes, such as cell differentiation. But if nutrients become available, the pathway is inhibited and the tissue can resume normal development.