The Transcription Factor ATF4 Is an Essential Mediator of Skeletal Muscle Atrophy

Skeletal muscle atrophy is a common and debilitating condition that requires widespread changes in skeletal muscle gene expression. However, the transcriptional regulatory factors that mediate muscle atrophy are incompletely understood. Here, we examined the potential role of ATF4, a stress‐responsive bZIP transcription factor that is induced in atrophying muscle. We found that ATF4 overexpression in mouse skeletal muscle was sufficient to induce muscle fiber atrophy. To determine if ATF4 is required for muscle atrophy, we generated and studied mice lacking ATF4 specifically in striated muscle (ATF4 mKO mice). ATF4 mKO mice were phenotypically normal under baseline conditions, however they lost ≈ 50% less muscle in response to two distinct muscle atrophy stimuli (fasting and hindlimb immobilization), indicating resistance to muscle atrophy. To determine if ATF4 promotes muscle atrophy by altering protein metabolism, we performed metabolic labeling studies in C2C12 skeletal myotubes, and found that ATF4 reduced protein synthesis and increased proteolysis, leading to myotube atrophy. Collectively, these data indicate that ATF4 is an essential mediator of muscle atrophy, and suggest that ATF4 reduces protein synthesis, induces proteolysis and promotes muscle atrophy by inducing one or more downstream target genes. This work was supported by the NIH and Department of Veterans Affairs.