Reflections on metabolism and skeletal muscle stem cells

The last few months have been a bit of a whirlwind at work, with plenty of successes to celebrate – the biggest of which has been the acceptance and publication of my postdoctoral research in Cell Stem Cell  (Ryall et al. 2015) investigating the process of metabolic reprogramming in skeletal muscle stem cells. This project began in 2008 in Dr Vittorio Sartorelli’s Laboratory of Muscle Stem Cells & Gene Regulation, when we noticed that there was a distinct metabolic gene profile in quiescent compared to proliferating muscle stem cells. What was particularly clear was the increased expression of glycolytic genes in the proliferating population (nearly every glycolytic enzyme was increased 2-20 fold). A similar upregulation can be observed in other previously published datasets, such as those from Margaret Buckingham and Tom Rando. This shift towards glycolysis is not unexpected in a proliferating cell population, and similar changes in metabolism have been observed in other stem cell and cancer cell populations. One of the reasons for this change is the requirement for new biomass (nucleotides, proteins and phospholipids for the generation of new cells, see here and here for recent reviews). However, what was particularly exciting was the link between this change in metabolism, gene transcription, and cell identity. We observed that the increase in glycolysis led to a reduction in the availability of NAD (a substrate required for the deactylase activity of SIRT1) and, as a result, an increase in the acetylation of one of the histone targets of SIRT1, histone H4 lysine 16 (H4K16). Using the Pax7cre X SIRT1fl/fl mouse model we could demonstrate elevated global H4K16ac in skeletal muscle stem cells, while culturing cells in galactose based growth media (instead of glucose) could prevent/delay the decline in NAD and H4K16ac. These results suggest that skeletal muscle stem cells can undergo a process of metabolic reprogramming during activation, and clearly link metabolism to cell identity (see our graphical abstract below).

While the last two-decades have focused extensively on the molecular revolution, and defining the transcriptional networks that regulate skeletal muscle stem cell identity and the processes of activation and proliferation, I expect the next decade to reveal the underlying cellular signals that initiate and regulate these networks. I’m excited about the role metabolism may play in regulating these processes, particularly the importance of metabolite availability (NAD for SIRT mediated deacetylation, acetyl-coA for acetylation, methionine for DNA/histone etc).

Refers to Ryall JG, Dell’Orso S, Derfoul A, Juan A, Zare H, Feng X, Clermont D, Koulnis M, Gutierrez-Cruz G, Fulco M, Sartorelli V (2015). The NAD+-Dependent SIRT1 Deacetylase Translates a Metabolic Switch into Regulatory Epigenetics in Skeletal Muscle Stem Cells. Cell Stem Cell Feb 5;16(2):171-183.