Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism

Abstract

SR.Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism. Am J Physiol Endocrinol Metab 311: E157-E174, 2016. First published May 17, 2016; doi:10.1152/ajpendo.00059.2016.-Since its discovery, the protein regulated in development and DNA damage 1 (REDD1) has been implicated in the cellular response to various stressors. Most notably, its role as a repressor of signaling through the central metabolic regulator, the mechanistic target of rapamycin in complex 1 (mTORC1) has gained considerable attention. Not surprisingly, changes in REDD1 mRNA and protein have been observed in skeletal muscle under various physiological conditions (e.g., nutrient consumption and resistance exercise) and pathological conditions (e.g., sepsis, alcoholism, diabetes, obesity) suggesting a role for REDD1 in regulating mTORC1-dependent skeletal muscle protein metabolism. Our understanding of the causative role of REDD1 in skeletal muscle metabolism is increasing mostly due to the availability of genetically modified mice in which the REDD1 gene is disrupted. Results from such studies provide support for an important role for REDD1 in the regulation of mTORC1 as well as reveal unexplored functions of this protein in relation to other aspects of skeletal muscle metabolism. The goal of this work is to provide a comprehensive review of the role of REDD1 (and its paralog REDD2) in skeletal muscle during both physiological and pathological conditions. muscle mass; RTP801; DDIT4; dig2 MAINTAINING SKELETAL MUSCLE MASS is of critical importance to many groups of people, ranging from athletes trying to accrete muscle protein to individuals trying to minimize protein loss with catabolic diseases such as cancer, sarcopenia, HIV/AIDS, sepsis, alcoholism, and diabetes. It is widely accepted that an increase in muscle mass and strength enhances physical performance in young, healthy individuals (16,47,97), and maintenance of skeletal muscle mass and strength in catabolic states is associated with decreased mortality (56,80,91,94,107). Moreover, in many catabolic conditions, current nutritional and pharmacological interventions are unable to prevent or reverse the erosion of muscle mass, thus presenting a barrier to improved patient care (122, 123). Therefore, a more complete understanding of how skeletal muscle mass is regulated is central to minimize its loss and/or speed recovery following disease in which muscle mass is compromised.The protein regulated in development and DNA damage 1 (REDD1) has been identified as a key regulator of skeletal muscle mass. For example, skeletal muscle-specific overexpression of REDD1 via electroporation reduces muscle fiber cross-sectional area (CSA) (35), and using mice with a global disruption of the REDD1 gene [hereafter referred to as REDD1 knockout (KO) mice] has implicated REDD1 as an important protein in muscle metabolism under both physiological and pathological conditions. As a thorough phenotypic description of the skeletal muscle from mice with ...

Restorative Mechanisms Regulating Protein Balance in Skeletal Muscle During Recovery From Sepsis

“…Likewise, there was no change in Thr172-phosphorylated AMPK between groups (Figure 6E). Finally, in contrast, there was more than a 50% decrease in REDD1, an mTORC1 inhibitory protein (16), in muscle during sepsis-recovery (Figure 6F). …”

Differential gene expression analysis reveals novel genes and pathways in pediatric septic shock patients

“…PERSEVERE-XP study had also identified DDIT4 gene directly related to TP53 7 . DDIT4 (REDD1) is increased in the septic shock and can negatively regulate mTORC1 activity and plays an important role in energy homeostasis 21 . We found CCL3 as the second-most significantly up-regulated chemokine, a fundamental component of the acute-phase response to endotoxin in humans and regulates the leukocyte activation and trafficking 32 .…”

DNA Damage Inducible Transcript 4 Gene: The Switch of the Metabolism as Potential Target in Cancer

“…Moreover, it is also upregulated by other chemical molecules, such as glucocorticoids ( 21 , 26 , 27 ), dopaminergic neurotoxins ( 28 ), endoplasmic reticulum stress inducers ( 21 , 29 ), DNA damage agent etoposide ( 21 ), and arsenite ( 30 ). Conversely, DDIT4 expression decreases by testosterone, acute resistance exercise, refeeding/nutrient consumption, and suppressed mTORC1 ( 31 ).…”