REDD1 Reduces Muscle Metabolism to Foster Adaptation under Fasting

Abstract : Aims and background : Regulated in Development and DNA Damage 1 (REDD1) is a stress‐induced protein responsible for the inhibition of the Akt/mTORC1 pathway. This pathway integrates energetic status and oxygen availability to promote protein and glycogen synthesis as well as mitochondrial biogenesis. REDD1 is expressed in response to exercise, hypoxia or fasting and has been observed in the mitochondrial fraction in vitro. Our aim is to characterize the role of REDD1 in skeletal muscle under energetic challenge. Methods and results : Wild‐type (WT) and REDD1 knockout (KO) mice were deprived of food for 16h and immediately killed before gastrocnemius and tibialis anterior muscles sampling. We observed an overactivation of the metabolic sensor AMPK and a greater glycogen depletion in skeletal muscle of REDD1 KO mice after fasting. In addition, REDD1 deficient mice displayed exacerbation of skeletal muscle atrophy in response to food deprivation compared to WT animals. We then used dexamethasone treatment to induce REDD1 protein expression and showed for the first time that REDD1 is (partly) localized at the mitochondrial‐associated endoplasmic reticulum membranes (MAM) of skeletal muscle fibers, where it is able to inhibit the Akt/mTORC1 pathway. Indeed, REDD1 binds to and reduces the interaction of MAM protein components, resulting in decreased mitochondrial O2 consumption and protein synthesis. Conclusions : Sustained activity of the Akt/mTORC1 pathway is known to promote anabolic processes and therefore to increase ATP consumption. Our results supports that REDD1 deletion contribute to maintain high fuel demand that in turn leads to skeletal muscle atrophy under fasting. We propose here that a physiological role for REDD1 is to foster skeletal muscle acclimatization during energetic challenges via reduction of O2 and ATP consumption assigned to synthesis processes. Support or Funding Information : This work was supported by the Agence Française de Lutte contre le Dopage (grant #4299).