Metabolism of glucose and glutamine is critical for skeletal muscle stem cell activation

Abstract

Injury to muscle tissue induces the resident, quiescent, skeletal muscle stem cells (MuSCs) to activate - to exit quiescence and enter the cell cycle. Previous work has shown that MuSC activation is associated with significant metabolic changes, however the substrates that MuSCs consume to support activation are poorly understood. Here, we show that MuSCs generate the majority of their energy through mitochondrial respiration, and that oxidative phosphorylation is required for MuSC activation. Furthermore, we have found that while glucose, glutamine, and fatty acids all significantly, and roughly equally, contribute to ATP production in MuSCs during activation, they do not have equal functional role in the dynamics of MuSC activation. Pharmacologic suppression of glycolysis, using 2-deoxy-D-glucose, or glutaminolysis, using BPTES, significantly impairs MuSC cell cycle entry. However, etomoxir-mediated inhibition of mitochondrial fatty acid transport has minimal effect on MuSC cell cycle progression. Our findings suggest that apart from their roles in fueling ATP production by the mitochondria, glucose and glutamine may generate metabolic intermediates needed for MuSC activation.

A cell cycle-linked mechanism for the glutamine driven establishment of stem cell fate

“…The critical role of glutamine in stimulating PASK nuclear translocation prompted us to examine the role of glutamine metabolism in various stages of self-renewal and differentiation. As expected, based on previous reports (Ahsan et al, 2020; Shang et al ., 2020), glutamine withdrawal in cultured myoblasts significantly reduced proliferation (Figure 5A). The glutamine withdrawn cells were significantly enlarged and remained alive in cell culture for at least 4 days (Figure 5A).…”

Fructose 1,6-bisphosphate sensing by pyruvate kinase isozymes M2 (PKM2) controls MyoD stability and myogenic differentiation

“…Finally, myoblasts turn on the 80 transcription factor myogenin (MyoG), a marker of terminal differentiation, and exit the cell cycle 81 to fuse into myotubes. Previous studies have shown that the glucose promotes activation of 82 quiescent muscle stem cells and differentiation of myoblasts in part by regulating histone acetylation , Yucel et al, 2019, Ahsan et al, 2020, Theret et al, 2017. In differentiated myotubes, glucose inhibits the Foxo transcription factors whose activity induces the 85 expression of muscle-specific ubiquitin ligases that result in atrophy (Sandri et al, 2004, Meng et (which was not certified by peer review) is the author/funder.…”