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Transient HIF2A inhibition promotes satellite cell proliferation and muscle regeneration
Liwei Xie, … , Jarrod A. Call, Hang Yin
Liwei Xie, … , Jarrod A. Call, Hang Yin
Published March 13, 2018
Citation Information: J Clin Invest. 2018;128(6):2339-2355. https://doi.org/10.1172/JCI96208.
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Research Article Muscle biology Article has an altmetric score of 32

Transient HIF2A inhibition promotes satellite cell proliferation and muscle regeneration

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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.

Authors

Liwei Xie, Amelia Yin, Anna S. Nichenko, Aaron M. Beedle, Jarrod A. Call, Hang Yin

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Figure 3

Genetic ablation of HIF2A in QSCs leads to transient activation, proliferation, and differentiation of SCs.

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Genetic ablation of HIF2A in QSCs leads to transient activation, prolife...
(A) Timeline of genetic ablation of HIF2A in QSCs. (B) Representative images of myofibers from SC-HIF2AKO mice and control littermates (n >50 myofibers from 5 mice/group; 10 dpr). Immunofluorescence of Pax7 (red), HIF2A (green), MyoD (purple), and DAPI (blue) staining revealed HIF2A–MyoD+ and HIF2A+MyoD– SCs (arrowheads) in SC-HIF2AKO and control mice, respectively. Scale bar: 10 μm. (C) Number of HIF2A+ and HIF2A– SCs per myofiber (10 dpr). (D) Number of MyoD– and MyoD+ SCs per myofiber (10 dpr). (E) Timeline characterizing SC proliferation after HIF2A ablation in QSCs. (F) Representative cross-sectional images of TA muscles from SC-HIF2AKO mice and control littermates (n = 6 mice/group; 16 dpr). Immunofluorescence of Pax7 (red), Ki67 (green), EdU (purple), and DAPI (blue) staining revealed an increase in Ki67+EdU+ SCs (arrowheads) in SC-HIF2AKO mice. Scale bar: 20 μm. (G) Number of Ki67– and Ki67+ SCs per TA section. (H) Number of EdU– and EdU+ SCs per TA section. (I) Timeline for tracing SC fates after HIF2A ablation in QSCs. (J) Representative images of TA muscles from SC-HIF2AKO-INTACT and control SC-INTACT mice (n = 6 mice/group; 16 dpr). Immunofluorescence of nmGFP, Pax7, laminin B2, and DAPI revealed increased nmGFP+Pax7+ SCs (arrowheads) and nmGFP+Pax7– myonuclei (asterisks) in SC-HIF2AKO-INTACT mice. Scale bar: 20 μm and 5 μm (insets). Inset images show that both nmGFP+Pax7+ SCs and nmGFP+Pax7– myonuclei are adjacent to the basal lamina. (K) Number of nmGFP+Pax7+ SCs and nmGFP+Pax7– myonuclei per TA section. (L) Number of nmGFP+myogenin+ differentiating SCs per EDL myofiber (16 dpr). **P < 0.01 and ***P < 0.005, by 2-sided Student’s t test. Data represent the mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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