Glucocorticoid-dependent REDD1 expression reduces muscle metabolism to enable adaptation under energetic stress

Skeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following...

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Bibliographic Details
Published in:	BMC biology 2018-06, Vol.16 (1), p.65-65, Article 65
Main Authors:	Britto, Florian A, Cortade, Fabienne, Belloum, Yassine, Blaquière, Marine, Gallot, Yann S, Docquier, Aurélie, Pagano, Allan F, Jublanc, Elodie, Bendridi, Nadia, Koechlin-Ramonatxo, Christelle, Chabi, Béatrice, Francaux, Marc, Casas, François, Freyssenet, Damien, Rieusset, Jennifer, Giorgetti-Peraldi, Sophie, Carnac, Gilles, Ollendorff, Vincent, Favier, François B
Format:	Article
Language:	eng
Subjects:	Adaptation AKT protein Analysis Arthritis ATP Atrophy Biosynthesis Cancer Cellular signal transduction Corticosteroids Diabetes mellitus DNA damage Electron transport Endoplasmic reticulum Energy expenditure Exercise Fasting Gene expression Glucocorticoids Glycogen Health aspects Hexokinase Hypoxia Kinases Life Sciences Mammals Membranes Metabolism Mitochondria Muscle function Muscles Musculoskeletal system Phosphorylation Physiology Protein biosynthesis Protein synthesis Proteins Respiration Rodents Secretion Signal transduction Signaling Skeletal muscle Stress (Physiology) Stresses
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Summary:	Skeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following glucocorticoid secretion, which is a component of energy stress responses. Unexpectedly, we show here that REDD1 instead limits muscle loss during energetic stresses such as hypoxia and fasting by reducing glycogen depletion and AMPK activation. Indeed, we demonstrate that REDD1 is required to decrease O and ATP consumption in skeletal muscle via reduction of the extent of mitochondrial-associated endoplasmic reticulum membranes (MAMs), a central hub connecting energy production by mitochondria and anabolic processes. In fact, REDD1 inhibits ATP-demanding processes such as glycogen storage and protein synthesis through disruption of the Akt/Hexokinase II and PRAS40/mTORC1 signaling pathways in MAMs. Our results uncover a new REDD1-dependent mechanism coupling mitochondrial respiration and anabolic processes during hypoxia, fasting, and exercise. Therefore, REDD1 is a crucial negative regulator of energy expenditure that is necessary for muscle adaptation during energetic stresses. This present study could shed new light on the role of REDD1 in several pathologies associated with energetic metabolism alteration, such as cancer, diabetes, and Parkinson's disease.
ISSN:	1741-7007 1741-7007