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J Biol Chem. 2016 Aug 19;291(34):17496-17509. doi: 10.1074/jbc.M116.740308. Epub 2016 Jun 29.

Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4.

Bullard SA1,2,3,4, Seo S5, Schilling B6, Dyle MC1,2,3,4,7, Dierdorff JM1,2,3,4, Ebert SM1,2,3,4,7, DeLau AD1,2,3,4, Gibson BW6,8, Adams CM9,2,3,4,7.

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From the Department of Internal Medicine.
Fraternal Order of Eagles Diabetes Research Center, and.
Departments of Molecular Physiology and Biophysics and.
the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246.
Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa 52242.
the Buck Institute for Research on Aging, Novato, California 94945, and.
Emmyon, Inc., Coralville, Iowa 52241.
the Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94143.
From the Department of Internal Medicine,


Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level.


Gadd45a; MEKK4; aging; mass spectrometry (MS); muscle; muscle atrophy; skeletal muscle; skeletal muscle metabolism

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