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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 1

Hexim1+/– muscles exhibit larger size and enhanced function after regeneration.

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Hexim1+/– muscles exhibit larger size and enhanced function after regen...
(A) Model of BaCl2-induced muscle injury. Dystrophin staining outlines muscle sarcomeres. Scale bar: 80 μm. (B) Injured and contralateral control TA muscles 50 days after injury. (C) Muscle wet weights, (D) cross-section areas, and (C and D) their injured-to-control ratios 50 days after injury (n = 12). (E) Representative plots of tetanic force production of injured and contralateral control TA muscles. (F) Absolute tetanic forces, (G) normalized tetanic forces, and (F and G) their injured-to-control ratios 10 weeks after injury (n = 3 [WT] or 6 [Hexim1+/–]). (H) Muscle sections 50 days after injury stained for dystrophin (red). Scale bar: 80 μm. (I) Average numbers of muscle fibers per section, (J) average individual myofiber sizes, and (K) average numbers of myonuclei per 100 muscle fibers 50 days after injury (n = 6). (L) Col1a2 mRNA levels 4 days after injury (n = 3). Statistical significance in scatter plots was assessed by a 2-tailed paired Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.

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

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