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Differential cell survival outcomes in response to diverse amino acid stress

ABSTRACT: Amino acid (AA) detection is fundamental for cellular function, balancing translation demands, biochemical pathways, and signaling networks. While the GCN2 and mTORC1 pathways are known to regulate AA sensing, the global cellular response to AA deprivation remains poorly understood, particularly in non-transformed cells, which may exhibit distinct adaptive strategies compared to cancer cells. Here we employed murine pluripotent embryonic stem (ES) cells as a model system to dissect cellular responses to AA stress. Using multi-omics analyses over an extended time course, we examined the effects of arginine (Arg) and leucine (Leu) deprivation, uncovering extensive yet non-lethal proteomic, phosphoproteomic, transcriptomic, and metabolomic adaptations, including increased lysosome production. We found that Arg or Leu starvation induces reversible cell cycle exit, promoting a quiescent state that enhances resistance to cytotoxic stressors. By contrast, cysteine (Cys) and threonine (Thr) deprivation led to cell death via distinct pathways: ferroptosis for Cys starvation, while Thr deprivation triggered a previously uncharacterized form of cell death, which could be entirely suppressed by methionine (Met) co-starvation, mTOR or translational inhibition. These findings suggest that ES cells implement specialized survival strategies in response to different AA limitations, highlighting their ability to reprogram cellular biochemistry under nutrient stress.

ORGANISM(S): Mus musculus

PROVIDER: GSE291532 | GEO | 2025/09/01

REPOSITORIES: GEO

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Project description:Skeletal muscle atrophy is dictated by the balance between protein synthesis and protein breakdown, known as proteostasis. With advanced age, muscle atrophy contributes to development of co-morbidities, loss of strength and independence, and all-cause mortality. Aging also coincides with the accumulation of senescent cells within skeletal muscle that produce inflammatory products, known as the senescence associated secretory phenotype. Previously, we found that a metformin + leucine (MET+LEU) combination treatment had synergistic effects in aged mice to improve skeletal muscle structure and function during disuse atrophy. Therefore, the objective of this study was to determine the mechanisms by which MET+LEU exhibits muscle atrophy protection in vitro and if this occurs through cellular senescence. C2C12 myoblasts differentiated into myotubes were used to determine MET+LEU mechanisms during serum-deprivation (SD) atrophy. Single myofibers were isolated from aged (22-23 mo) C57Bl6/J mice, and human primary myoblasts were extracted from a healthy older adult donor. 25 + 125 µM MET+LEU treatment increased differentiation of myotubes and prevented SD induced atrophy. Low concentration (0.1 + 0.5 µM) MET+LEU had unique effects to prevent myotube atrophy and cause transcriptional reprogramming compared to individual therapies. SD increased inflammatory and cellular senescence pathways that was reversed with MET+LEU treatment. SD resulted in dysregulated proteostasis that was rescued with MET+LEU, and proteasome inhibition with MG-132 also rescued myotube atrophy. Cellular senescence transcriptional pathways and markers increased by SD were reversed with MET+LEU treatment, and dasatinib + quercetin (D+Q) senolytic treatment prevented myotube atrophy similar to MET+LEU. In aged myofibers, MET+LEU prevented SD atrophy, and in human primary myotubes MET+LEU prevented reductions in myonuclei fusion. These data provide evidence that MET+LEU has muscle cell intrinsic properties to prevent atrophy by reversing senescence and improving proteostasis

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Differential cell survival outcomes in response to diverse amino acid stress

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