REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

Abstract

Ferry A, Bonnieu A, Ollendorff V, Favier FB. REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy. Am J Physiol Endocrinol Metab 307: E983-E993, 2014. First published October 14, 2014 doi:10.1152/ajpendo.00234.2014.-REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wildtype (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoidinduced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy. regulated in development and DNA damage response 1; protein synthesis; mechanistic target of rapamycin; autophagy; glucocorticoids; proline-rich Akt substrate of 40 kDa

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

“…However, this original study provided only associative and not causal evidence, thereby increasing the importance of later work that REDD1 KO mice to determine the link between REDD1 and glucocorticoid-induced muscle atrophy. As described therin, REDD1 KO mice (20-wk-old female) were resistant to the loss in muscle mass and muscle fiber CSA induced by 7 days of dexamethasone treatment compared with WT mice (12). Furthermore, the acute (5 h) dexamethasoneinduced decrease in protein synthesis as well as phosphorylation of 4E-BP1 (Thr 37/46 ) and ribosomal protein S6 (rpS6; Ser 240/244 ) was offset in REDD1 KO mice (12).…”

“…As described therin, REDD1 KO mice (20-wk-old female) were resistant to the loss in muscle mass and muscle fiber CSA induced by 7 days of dexamethasone treatment compared with WT mice (12). Furthermore, the acute (5 h) dexamethasoneinduced decrease in protein synthesis as well as phosphorylation of 4E-BP1 (Thr 37/46 ) and ribosomal protein S6 (rpS6; Ser 240/244 ) was offset in REDD1 KO mice (12). Phosphorylation of rpS6 is commonly used to imply mTORC1 activity, as it lies directly downstream from p70S6K1 and will often exhibit more robust changes than p70S6K1 (Thr 389 ).…”

“…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 the global disruption of the REDD1 gene has been presented elsewhere (12), it will not be reiterated here. However, it should be noted that basal muscle mass was not different in these animals (12).…”

“…As a thorough phenotypic description of the skeletal muscle from mice with the global disruption of the REDD1 gene has been presented elsewhere (12), it will not be reiterated here. However, it should be noted that basal muscle mass was not different in these animals (12). Despite the growing realization of the diverse actions of REDD1, a comprehensive review of the literature pertaining to its importance specifically in skeletal muscle is lacking.…”

Global deletion ofBCATmincreases expression of skeletal muscle genes associated with protein turnover

“…For example, DNA damage-inducible transcript 4 (Ddit4, alias: Redd1) is a major inhibitor of mTOR during stress and a mediator of atrophy and target of glucocorticoids (13). Ddit4 gene expression was elevated almost threefold in the gastrocnemius of BCATm KO mice (Fig.…”