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

The Journal of clinical investigation (Impact Factor: 13.22). 10/2012; 122(11). DOI: 10.1172/JCI62818
Source: PubMed


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.

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    • "Nor was 7sk snRNA, a P-TEFb inhibitor (Yang et al., 2001; Nguyen et al., 2001). Interestingly the Hexim1, another component of the P-TEFb inhibitor complex (Li et al., 2005; Hong et al., 2012), and Sesn3 (Chen et al., 2010) genes were greatly enhanced following JQ1 exposure (Figure 3C). Next we tested female ESCs with various doses of JQ1. "
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    • "c o m / l o c a t e / y b b r c HEXIM1 was initially identified as the protein that inhibits proliferation of vascular smooth muscle cells and has been shown to be involved in cancers, AIDS, inflammation, skeletal muscle regeneration , hormonal actions, and cardiac hypertrophy. One of the major biological functions of HEXIM1 is suppression of positive transcription elongation factor b (P-TEFb), which is a protein complex composed of cyclin-dependent kinase 9 (CDK9) and cyclin T1 (CycT1), and plays a key role in regulation of RNA polymerase IIdependent transcription elongation [8] [9] [10] [11] [12]. HEXIM1 knockout mice exhibited LV hypertrophy during the late stages of fetal development, whereas heart-specific activation of P-TEFb provoked LV hypertrophy in mice [13] [14]. "
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