Fig. 4

MuSC fitness in relationship to cellular and environmental stress. Cell fates associated with increasing stress are indicated along the modified Yerkes-Dodson curve (white text). (Yellow zone) Optimal levels of cellular and environmental stress are required to maintain the quiescent MuSC pool (dark green cell). Activation of stress response pathways that inhibit protein synthesis, including phosphorylation of eIF2α (P-eIF2α) and TSC1 inhibition of mTORC1 signalling, are required for MuSC quiescence and self-renewal. In addition, a subset of quiescent MuSCs expressing PAX3 (PAX3) exhibit enhanced resistance to stress. Activation of stress response pathways in quiescent MuSCs are also illustrated by the presence of P-eIF2α-dependent RNA granules (orange foci). (Green zone) MuSCs with reduced cellular fitness are removed from the MuSC pool by spontaneous activation (blue cells) and contribution to the myofibre (fusing blue cell with the brown myofibre; myonuclei are indicated in purple). Genetic inactivation of P-eIF2α leads to activation and differentiation of MuSCs. Genetic inactivation of Tsc1 and exposure to the environmental pollutant TCDD leads to the G_alert state of early activation and/or full MuSC activation and differentiation. (Red zone) MuSCs that encounter severe stress, for example accumulating damage associated with aging, or proliferative stress associated with chronic muscle degeneration, are removed from the stem cell pool by the activation of cell senescence or death pathways (bloated red cell)