Transient HIF2A inhibition promotes satellite cell proliferation and muscle regeneration

Abstract

The remarkable regeneration capability of skeletal muscle depends on the coordinated proliferation and differentiation of satellite cells (SCs). The self-renewal of SCs is critical for long-term maintenance of muscle regeneration potential. Hypoxia profoundly affects the proliferation, differentiation, and self-renewal of cultured myoblasts. However, the physiological relevance of hypoxia and hypoxia signaling in SCs in vivo remains largely unknown. Here, we demonstrate that SCs are in an intrinsic hypoxic state in vivo and express hypoxia-inducible factor 2A (HIF2A). HIF2A promotes the stemness and long-term homeostatic maintenance of SCs by maintaining their quiescence, increasing their self-renewal, and blocking their myogenic differentiation. HIF2A stabilization in SCs cultured under normoxia augments their engraftment potential in regenerative muscle. Conversely, HIF2A ablation leads to the depletion of SCs and their consequent regenerative failure in the long-term. In contrast, transient pharmacological inhibition of HIF2A accelerates muscle regeneration by increasing SC proliferation and differentiation. Mechanistically, HIF2A induces the quiescence and self-renewal of SCs by binding the promoter of the Spry1 gene and activating Spry1 expression. These findings suggest that HIF2A is a pivotal mediator of hypoxia signaling in SCs and may be therapeutically targeted to improve muscle regeneration.

YY 1 regulates skeletal muscle regeneration through controlling metabolic reprogramming of satellite cells

“…In addition to directly controlling the expression of mitochondrial genes, we for the first time showed that YY1 could also modulate glycolytic pathway through stabilizing Hif1α protein, thus underpinning YY1 as a metabolic controller with dual functions simultaneously modulating two main bioenergetic pathways to facilitate the proliferative growth of SCs. Hif1α is emerging as a key regulator of glycolysis via direct trans‐activation of many glycolytic genes (Ito & Suda, ); here, we for the first elucidated its functionality and mechanism in regulating SC metabolism and extended findings from two prior reports (Yang et al , ; Xie et al , ). In the study by Yang et al , when both Hif1α and Hif2α genes were deleted by Pax7CreER, an obvious delay was observed during CTX injury‐induced muscle regeneration (Fig ); nevertheless, no single mutant was made to further investigate their separate roles.…”

“…To search for plausible mechanisms explaining their down‐regulation, we noticed that the majority of these genes, including Glut1, Hk2, Gpi, Pfkl, Pfkfb3, Aldoa, Eno1, Pkm, Ldha, and Pdk1 , are known trans‐activated targets of hypoxia‐inducible factor‐1 (Hif1α; Ito & Suda, ), raising an intriguing possibility that the compromised glycolysis in YY1 iKO cells is mediated by Hif1α. Xie et al () in fact recently demonstrated the possible induction of Hif1α in SC proliferation, which nevertheless needs to be confirmed and the exact mechanism behind its involvement in SC, remains unclear. Similar to YY1, an increase in Hif1α protein was observed in ASCs vs. FISCs (Fig EV5C), suggesting a potential promoting role during SC activation/proliferation.…”

Prolyl hydroxylase domain 2 reduction enhances skeletal muscle tissue regeneration after soft tissue trauma in mice

“…Herein, we provide evidence that stronger MyoD-expression is mediated via HIF-1 (Fig 2C), which supports recent findings by several groups [3,53,54] but contradicts a study that demonstrated MyoD degradation under hypoxia [55]. Considering a different pathophysiology in different methods of mechanical trauma, our findings support a promotion of satellite cell proliferation after mechanic muscle trauma which is regulated via HIF-1(α) [56]. Our results demonstrate that the higher regenerative potential and earlier trauma regeneration is associated with reduced PHD2 activity and higher HIF-1 expression ( Fig 3A and 3B, respectively), which leads to an earlier and stronger activation of myogenic factors.…”

Pro-myogenic small molecules revealed by a chemical screen on primary muscle stem cells

“…However, prolonged inhibition of RET (and by extension, the prolonged inhibition of quiescence and self-renewal) would be expected to cause greater numbers of activated satellite cells initially, before eventually depleting the satellite cell pool, as was seen by Li et al following genetic inhibition of RET signaling for 1 month. This exact pattern of expansion followed by exhaustion was also shown for HIF2A where transient genetic or pharmacological inhibition leads to increased satellite cell numbers and improved regeneration, but sustained inhibition leads to satellite cell depletion and impaired regeneration [70].…”