Myogenin and Class II HDACs Control Neurogenic Muscle Atrophy by Inducing E3 Ubiquitin Ligases

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell (Impact Factor: 32.24). 10/2010; 143(1):35-45. DOI: 10.1016/j.cell.2010.09.004
Source: PubMed


Maintenance of skeletal muscle structure and function requires innervation by motor neurons, such that denervation causes muscle atrophy. We show that myogenin, an essential regulator of muscle development, controls neurogenic atrophy. Myogenin is upregulated in skeletal muscle following denervation and regulates expression of the E3 ubiquitin ligases MuRF1 and atrogin-1, which promote muscle proteolysis and atrophy. Deletion of myogenin from adult mice diminishes expression of MuRF1 and atrogin-1 in denervated muscle and confers resistance to atrophy. Mice lacking histone deacetylases (HDACs) 4 and 5 in skeletal muscle fail to upregulate myogenin and also preserve muscle mass following denervation. Conversely, forced expression of myogenin in skeletal muscle of HDAC mutant mice restores muscle atrophy following denervation. Thus, myogenin plays a dual role as both a regulator of muscle development and an inducer of neurogenic atrophy. These findings reveal a specific pathway for muscle wasting and potential therapeutic targets for this disorder.

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    • "It is interesting that the Dach2-Hdac9 signaling system regulates a variety of activity-dependent processes like muscle reinnervation, muscle metabolism, muscle fiber type determination and muscle atrophy (Mejat et al., 2005; Tang and Goldman, 2006; Tang et al., 2006; Tang et al., 2009; Moresi et al., 2010; Macpherson et al., 2011). The coordinate activation of these processes in denervated muscle may help promote muscle survival and reinnervation after nerve damage. "
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    • "ed upon denervation ( Legerlotz and Smith , 2008 ) . On similar lines , Myogenin is also expressed in fibers in the absence of a regenerative response ( Hughes et al . , 1993 ) , and can act as an essential mediator of neurogenic atrophy by regulating the expression of Murf1 and Atrogin - 1 within the fiber , thereby promoting muscle proteolysis ( Moresi et al . , 2010 ) . Alterations in the myogenic program have also been described in cachexia , a complex metabolic syndrome characterized by a loss of muscle mass , which is initiated by underlying illnesses of different nature , such as cancer , CHF , COPD , CKD , burns , chronic infection and sepsis ( Evans et al . , 2008 ; Fearon et al . , 2012 ) . "
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