Regeneration of adult tissues depends on stem cells that are primed to enter a differentiation program, while remaining quiescent. How these two characteristics can be reconciled is exemplified by skeletal muscle in which the majority of quiescent satellite cells transcribe the myogenic determination gene Myf5, without activating the myogenic program. We show that Myf5 mRNA, together with microRNA-31, which regulates its translation, is sequestered in mRNP granules present in the quiescent satellite cell. In activated satellite cells, mRNP granules are dissociated, relative levels of miR-31 are reduced, and Myf5 protein accumulates, which initially requires translation, but not transcription. Conditions that promote the continued presence of mRNP granules delay the onset of myogenesis. Manipulation of miR-31 levels affects satellite cell differentiation ex vivo and muscle regeneration in vivo. We therefore propose a model in which posttranscriptional mechanisms hold quiescent stem cells poised to enter a tissue-specific differentiation program.

Regeneration of adult tissues depends on somatic stem cells that remain quiescent yet are primed to enter a differentiation program. The molecular pathways that prevent activation of these cells are not well understood. Using mouse skeletal muscle stem cells as a model, we show that a general repression of translation, mediated by the phosphorylation of translation initiation factor eIF2α at serine 51 (P-eIF2α), is required to maintain the quiescent state. Skeletal muscle stem cells unable to phosphorylate eIF2α exit quiescence, activate the myogenic program, and differentiate, but do not self-renew. P-eIF2α ensures in part the robust translational silencing of accumulating mRNAs that is needed to prevent the activation of muscle stem cells. Additionally, P-eIF2α-dependent translation of mRNAs regulated by upstream open reading frames (uORFs) contributes to the molecular signature of stemness. Pharmacological inhibition of eIF2α dephosphorylation enhances skeletal muscle stem cell self-renewal and regenerative capacity.

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