Altered nutrient response of mTORC1 as a result of changes in REDD1 expression: effect of obesity vs. REDD1 deficiency

Williamson, David L.; Li, Zhuyun; Tuder, Rubin M.; Feinstein, Elena; Kimball, Scot R.; Dungan, Cory M.

doi:10.1152/japplphysiol.01350.2013

Cited by 42 publications

(77 citation statements)

References 81 publications

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“…Recent work supports an emerging role for REDD1 in the regulation of skeletal muscle metabolism and insulin action in obesity (32,100,108,133,134). It was initially observed that under fasting conditions skeletal muscle REDD1 mRNA and/or protein were higher in the gastrocnemius of male obese mice compared with lean mice.…”

Section: E162mentioning

confidence: 74%

“…This was unexpectedly associated with reduced formation of the TSC1/2 complex and increased mTORC1 activation as assessed by a reduction in the binding of raptor with mTOR (28). Additional analysis showed that REDD1 protein was elevated in the triceps surae muscle complex of obese male ob/ob mice compared with the values observed in the muscle of lean mice in both the fasted and fed states (134). Furthermore, male mice lacking REDD1 were partially resistant to weight gain induced by 2 mo of high-fat feeding, supporting a relationship between REDD1 and obesity development (134).…”

Section: E162mentioning

confidence: 87%

“…Additionally, the role of REDD1 in the regulation of mTORC1 signaling and protein synthesis at later time points following refeeding (i.e., postprandial or postabsorptive) is also unknown. Understanding the role of REDD1 at these later time points is potentially important, as it was observed that phosphorylation of p70S6K1 (Thr 389 ) was lower in the gastrocnemius of male REDD1 KO mice compared with WT mice when assessed in the freely fed state, suggesting an alternative metabolic function of REDD1 (134). Furthermore, the abovementioned studies were performed in male rodents, and whether a similar REDD1 response occurs in skeletal muscle of female mice is unknown.…”

Section: Role Of Redd1 During Physiological Conditionsmentioning

confidence: 99%

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

Gordon

Steiner

Williamson

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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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 ...

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Section: E162mentioning

confidence: 74%

Section: E162mentioning

confidence: 87%

Section: Role Of Redd1 During Physiological Conditionsmentioning

confidence: 99%

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

Gordon

Steiner

Williamson

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…Moreover, the same stressors that upregulate REDD1 expression, such as glucocorticoids (75), DNA damage (42), endoplasmic reticulum stress (61,76), and hypoxia (7,65), are the same stressors that are observed in obese individuals (1,16,47) and inhibit mTOR function (7,23,75). Work from our laboratory (20,79) and others (14,47) support the emerging role of REDD1 in metabolism and insulin action. Specifically, we report that obesity-associated elevations in REDD1 expression blunts skeletal muscle Akt and mTOR signaling in response to nutrients (79).…”

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confidence: 69%

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

Williamson

Dungan

Mahmoud

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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-The objective of this study was to establish whether alterations in the REDD1-mTOR axis underlie skeletal muscle insensitivity to insulin in Type 2 diabetic (T2D), obese individuals. Vastus lateralis muscle biopsies were obtained from lean, control and obese, T2D subjects under basal and after a 2-h hyperinsulinemic (40 mU·m Ϫ2 ·min Ϫ1 )-euglycemic (5 mM) clamp. Muscle lysates were examined for total REDD1, and phosphorylated Akt, S6 kinase 1 (S6K1), 4E-BP1, ERK1/2, and MEK1/2 via Western blot analysis. Under basal conditions [(-) insulin], T2D muscle exhibited higher S6K1 and ERK1/2 and lower 4E-BP1 phosphorylation (P Ͻ 0.05), as well as elevations in blood cortisol, glucose, insulin, glycosylated hemoglobin (P Ͻ 0.05) vs. lean controls. Following insulin infusion, whole body glucose disposal rates (GDR; mg/kg/ min) were lower (P Ͻ 0.05) in the T2D vs. the control group. The basal-to-insulin percent change in REDD1 expression was higher (P Ͻ 0.05) in muscle from the T2D vs. the control group. Whereas, the basal-to-insulin percent change in muscle Akt, S6K1, ERK1/2, and MEK1/2 phosphorylation was significantly lower (P Ͻ 0.05) in the T2D vs. the control group. Findings from this study propose a REDD1-regulated mechanism in T2D skeletal muscle that may contribute to whole body insulin resistance and may be a target to improve insulin action in insulin-resistant individuals.glucocorticoid; insulin resistance; mTOR; signaling TWO-THIRDS OF THE UNITED STATES has a 25% or greater prevalence of obesity (54), which places increased demand and cost on the health care system. Of the numerous comorbidities associated with obesity, the development of insulin resistance and Type 2 diabetes (T2D) are major concern for obese individuals, leading to overall reductions in metabolic flexibility (50). This becomes more of a concern, since the population of obese individuals is expanding in all age groups. Findings from the National Health and Nutrition Examination Survey data (68,69) show that skeletal muscle mass is fundamental for insulin sensitivity. Skeletal muscle mass is lower in the obese when expressed relative to total body mass vs. a lean individual and has a high pervasiveness of ectopic lipid within skeletal muscle that contributes to reduced insulin action (27,50). Among other factors, elevated endogenous glucocorticoid concentrations contribute to insulin resistance in the obese and T2D (58, 74).Insulin activation of the insulin receptor substrate 1 (IRS-1), phosphatidyl-inositol-3 kinase (PI3K), Ak strain transforming (Akt), and the ERK 1/2 pathways are essential for the regulation of cellular glucose uptake, proliferation, and growth. Akt and ERK1/2 activation increases GTPase function of the Ras homolog enriched in brain (Rheb) protein toward the mechanistic target of rapamycin (mTOR; also known as mammalian target of rapamycin) by inactivating the repressive effects of the tuberous sclerosis complex (TSC). The TSC complex remains central to the integration of signaling inputs from Akt, ERK1/2, and AMPK (32, 44,...

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“…In addition, it remains to be tested whether REDD1 is responsible for an alteration of the protein synthesis/degradation balance and a reduction in skeletal muscle mass in stress conditions. Moreover, it is not known whether REDD1 deletion affects muscle function and typology, although it does not seem to affect gastrocnemius muscle weight (50).…”

mentioning

confidence: 99%

REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

Britto

Begue

Rossano

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

103

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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

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Altered nutrient response of mTORC1 as a result of changes in REDD1 expression: effect of obesity vs. REDD1 deficiency

Cited by 42 publications

References 81 publications

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

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

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

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