Here, we discuss recent work focused on the role of activating transcription factor 4 (ATF4) in skeletal muscle atrophy.
Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression; however, the transcriptional regulatory proteins responsible for those changes are not yet well defined. Recent work indicates that some forms of muscle atrophy require ATF4, a stress-inducible bZIP transcription factor subunit that helps to mediate a broad range of stress responses in mammalian cells. ATF4 expression in skeletal muscle fibers is sufficient to induce muscle fiber atrophy and required for muscle atrophy during several stress conditions, including aging, fasting, and limb immobilization. By helping to activate specific genes in muscle fibers, ATF4 contributes to the expression of numerous mRNAs, including at least two mRNAs (Gadd45a and p21) that encode mediators of muscle fiber atrophy. Gadd45a promotes muscle fiber atrophy by activating the protein kinase MEKK4. p21 promotes atrophy by reducing expression of spermine oxidase, a metabolic enzyme that helps to maintain muscle fiber size under nonstressed conditions.
In skeletal muscle fibers, ATF4 is critical component of a complex and incompletely understood molecular signaling network that causes muscle atrophy during aging, fasting, and immobilization.
aDepartment of Internal Medicine
bDepartment of Molecular Physiology and Biophysics
cFraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa
dIowa City Veterans Affairs Medical Center, Iowa City
eEmmyon, Inc., Coralville, Iowa, USA
Correspondence to Christopher M. Adams, MD, PhD, University of Iowa, Iowa City, IA, USA. Tel: +1 319 353 5786; fax: +1 319 335 3865 e-mail: email@example.com