Conditional Loss of Pten in Myogenic Progenitors Leads to Postnatal Skeletal Muscle Hypertrophy but Age-Dependent Exhaustion of Satellite Cells

Skeletal muscle stem cells (satellite cells [SCs]) are normally maintained in a quiescent (G0) state. Muscle injury not only activates SCs locally, but also alerts SCs in distant uninjured muscles via circulating factors. The resulting GAlert SCs are adapted to regenerative cues and regenerate injured muscles more efficiently, but whether they provide any long-term benefits to SCs is unknown. Here, we report that embryonic myogenic progenitors lacking the phosphatase and tensin homolog (Pten) exhibit enhanced proliferation and differentiation, resulting in muscle hypertrophy but fewer SCs in adult muscles. Interestingly, Pten null SCs are predominantly in the GAlert state, even in the absence of an injury. The GAlert SCs are deficient in self-renewal and subjected to accelerated depletion during regeneration and aging and fail to repair muscle injury in old mice. Our findings demonstrate a key requirement of Pten in G0 entry of SCs and provide functional evidence that prolonged GAlert leads to stem cell depletion and regenerative failure. [Display omitted] •Loss of Pten in myoblasts leads to postnatal muscle hypertrophy•Pten null satellite cells are maintained in an “alert” state in adult resting muscle•Pten null satellite cells are defective in self-renewal and cannot reenter quiescence•Pten null GAlert satellite cells are depleted with age, leading to regenerative failure Yue et al. find that Pten is required for muscle stem cell (satellite cell) homeostasis. Pten deletion in embryonic myogenic progenitors leads to a reduction of postnatal satellite cells that are in an “alert” state. These GAlert satellite cells are defective in self-renewal and depleted with age, leading to regenerative failure.