
-   Chronic mTORC1 activation in skeletal muscle is linked with age-associated loss of muscle mass and strength, known as sarcopenia. mTORC1 promotes protein synthesis by activating S6Ks and inhibiting eIF4E-binding proteins (4EBPs). Muscle-specific over-expression of a 4EBP1 mutant transgene (4EBP1mt), which is resistant to mTORC1-mediated inhibition, ameliorates muscle loss with age and preserves muscle function by enhancing mitochondria activities. 4EBP1 activation relieved oxidative stress to prevent toxic aggregate accumulation in muscle and restored mitochondrial homeostasis and function. Thus, dysregulated 4EBP1 expression is relevant to skeletal muscle disease due to its role in regulating mitochondrial activity and lysosomal degradative capacity [PMID: 36398408].
-   Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity. Skeletal muscle-specific 4E-BP1 mediated metabolic protection directly through increased translation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and enhanced respiratory function [PMID: 26121750].
-   Amplification of the 4E-BP1 gene is one possible mechanism for its overexpression in tumors. The gene encoding 4E-BP1 is located at the chromosomal region 8p12, which is commonly amplified in breast cancer [PMID: 21748818].
-   Phosphorylated 4E-BP1 has been generally accepted as a marker of activated mTOR signaling. Seven phosphorylation sites have been identified in human 4E-BP1 [PMID: 22508483] and multiple kinases was involved in 4E-BP1 phosphorylation (such as mTORC1, GSK3beta, MAP kinase p38, ERK, ATM, and LRRK2). Hyperphosphorylation of 4E-BP1 at multiple sites may play an important role in its stabilization and overexpression. Hyperphosphorylation and overexpression of 4E-BP1 was widely reported in human cancers, and has been associated with a worse outcome in several malignancies. [PMID: 26901143].
-   In advanced cancer, 4E-BP1 may act as a hypoxia-inducible switch, promoting cap-independent over cap-dependent translation, resulting in selective translation of IRES-containing mRNAs such as VEGF, HIF1alpha, and Bcl2 that promote tumor angiogenesis, survival [PMID: 17996713, PMID: 18708753], and may be involved in the PI3K/mTOR inhibitor adaptive resistance in matrix-attached cancer cells [PMID: 22340595].

## Summary

The EIF4EBP1 gene encodes a protein that regulates translation initiation by interacting with eIF4E [CS: 10]. When hypophosphorylated, EIF4EBP1 binds to EIF4E, inhibiting translation initiation [CS: 10]. This inhibition is reversed when EIF4EBP1 is hyperphosphorylated, allowing translation to proceed [CS: 10]. In the context of skeletal muscle, dysregulation of EIF4EBP1 impacts muscle protein synthesis, a critical factor in maintaining muscle mass and function [CS: 9].

In situations of muscle stress or disease, such as in sarcopenia or muscle atrophy, the body responds by altering EIF4EBP1 activity [CS: 8]. For example, in hindlimb immobilization, a condition mimicking muscle disuse, there's an upregulation of EIF4EBP1, which may be a response to reduce energy expenditure on protein synthesis in muscles that are not actively being used [CS: 7]. Similarly, in conditions like sarcopenia, chronic mTORC1 activation leads to the phosphorylation and inactivation of EIF4EBP1, which would normally act to inhibit translation initiation [CS: 8]. This shift might be an attempt to maintain muscle protein synthesis in the face of age-related decline [CS: 7].
