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HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration
Peng Hong, … , Xian-Cheng Jiang, M.A.Q. Siddiqui
Peng Hong, … , Xian-Cheng Jiang, M.A.Q. Siddiqui
Published October 1, 2012
Citation Information: J Clin Invest. 2012;122(11):3873-3887. https://doi.org/10.1172/JCI62818.
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Research Article Muscle biology

HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration

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Abstract

The native capacity of adult skeletal muscles to regenerate is vital to the recovery from physical injuries and dystrophic diseases. Currently, the development of therapeutic interventions has been hindered by the complex regulatory network underlying the process of muscle regeneration. Using a mouse model of skeletal muscle regeneration after injury, we identified hexamethylene bisacetamide inducible 1 (HEXIM1, also referred to as CLP-1), the inhibitory component of the positive transcription elongation factor b (P-TEFb) complex, as a pivotal regulator of skeletal muscle regeneration. Hexim1-haplodeficient muscles exhibited greater mass and preserved function compared with those of WT muscles after injury, as a result of enhanced expansion of satellite cells. Transplanted Hexim1-haplodeficient satellite cells expanded and improved muscle regeneration more effectively than WT satellite cells. Conversely, HEXIM1 overexpression restrained satellite cell proliferation and impeded muscle regeneration. Mechanistically, dissociation of HEXIM1 from P-TEFb and subsequent activation of P-TEFb are required for satellite cell proliferation and the prevention of early myogenic differentiation. These findings suggest a crucial role for the HEXIM1/P-TEFb pathway in the regulation of satellite cell–mediated muscle regeneration and identify HEXIM1 as a potential therapeutic target for degenerative muscular diseases.

Authors

Peng Hong, Kang Chen, Bihui Huang, Min Liu, Miao Cui, Inna Rozenberg, Brahim Chaqour, Xiaoyue Pan, Elisabeth R. Barton, Xian-Cheng Jiang, M.A.Q. Siddiqui

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Figure 5

Hexim1+/– satellite cells exhibit enhanced proliferation over differentiation.

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Hexim1+/– satellite cells exhibit enhanced proliferation over different...
(A) Average numbers of cells per colony from 20 single cell–derived colonies. Data points represent days 1, 2, 3, and 4 of culture in GM (n = 6). (B) Histogram showing PKH26 signals of sorted cells cultured in GM for 1 or 4 days. (C) Single cell–derived colonies stained for Pax7 (green) and MyoD (red). Arrows indicate Pax7+MyoD– cells. Scale bar: 20 μm. (D) Percentages of cells in satellite cells cultured for 3 days in GM. (E) Muscle sections 4 days after injury stained for laminin (green) and myogenin (red). Laminin outlines regenerating myofibers, and myogenin marks differentiating myogenic cells. Scale bar: 100 μm. (F) Immunoblots of desmin and MHC in injured and contralateral control muscles 4 days after injury. (G) Myh3 mRNA levels 4 days after injury (n = 3). (H) Percentages of transplanted cells retaining satellite cell markers 3 days after transplantation. (I) Percentages of myogenin+ cells among PKH26+ cells 3 days after transplantation (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001. Plots were representative of 6 independent experiments.

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

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