
-   Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible gene REDD1/RTP801. Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia. REDD1 overexpression is sufficient to down-regulate S6K phosphorylation in a TSC1/TSC2-dependent manner [PMID: 15545625].
-   Changes in mTORC1 signaling were inversely proportional to alterations in the expression of the mTORC1 repressor, REDD1 [PMID: 18070882].
-   The induction of dig2 mRNA by dexamethasone appears to be mediated through the glucocorticoid receptor as it is blocked in the presence of RU486, a glucocorticoid receptor antagonist [PMID: 12736248].
-   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. REDD1 has been proposed to act by directly binding to and sequestering 14-3-3 proteins away from TSC2, leading to TSC2-dependent inhibition of mTORC1 [PMID: 20166753, PMID: 37653030, PMID: 16258273, PMID: 27189933].
-   REDD1/RTP801 gene is upregulated by hypoxia and induced by a variety of chemotherapeutic drugs. Overexpression of REDD1 may promote the apoptotic death of cancer cells and increases their sensitivity to ischemic injury and oxidative stress. In these processes, REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase and acts as an essential regulator of TOR activity through the TSC1/2 complex [PMID: 16258273, PMID: 17005863].
-   REDD1 instead limits muscle loss during energetic stresses such as hypoxia and fasting by reducing glycogen depletion and AMPK activation. 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 [PMID: 29895328].

## Summary

DDIT4, known as REDD1, plays a key role in skeletal muscle response to stress by modulating the mTOR pathway [CS: 8]. Its upregulation, seen in various stress conditions such as exposure to dexamethasone, cachexia, chronic hypoxia, or ALS, directly impacts the mTOR signaling pathway [CS: 7]. This impact is mediated through the inhibition of the TSC1-TSC2 complex [CS: 8]. Normally, TSC2 suppresses the GTPase RHEB, a crucial activator of mTORC1 [CS: 9]. When DDIT4 levels rise, it disrupts the interaction between TSC2 and 14-3-3 proteins, enhancing TSC2's inhibition of RHEB, which in turn leads to reduced mTORC1 activity [CS: 7]. The downregulation of mTORC1 conserves energy by reducing protein synthesis and muscle growth, a necessary adaptation during stress [CS: 8].

For example, in cachexia and ALS, the upregulated DDIT4 expression reflects a survival strategy where energy expenditure on muscle growth is minimized, redirecting resources to vital functions under systemic stress [CS: 8]. Similarly, in response to chronic hypoxia, increased DDIT4 expression and subsequent mTOR pathway inhibition lead to decreased muscle fiber cross-sectional area [CS: 7]. This adaptation is crucial for conserving energy in environments with lower oxygen availability [CS: 8]. Thus, DDIT4 acts as a regulatory node in skeletal muscle, modulating growth and energy use in response to various stressors through its intricate control over the mTOR pathway [CS: 8].
