Constitutive Activation of Skeletal Muscle mTORC1 Drives Pro-Inflammatory Gene Expression in Skeletal Muscle of Aged Mice.
What this study shows
In 27-month-old mice, inducible loss of Depdc5 (a negative regulator of mTORC1) in skeletal muscle raised inflammatory and immune-related gene expression and TNF-α protein, with shifts in metabolic and angiogenic pathways, but without a change in macrophage phenotype or capillary density. Dietary rapamycin partly reversed mTORC1 signalling and some transcriptional changes, including angiogenesis-related ones, but did not suppress the inflammation-related transcripts or protein. Boundary: one mouse model of genetic, constitutive mTORC1 activation in muscle of very old male mice; it shows that sustained activation is sufficient for these changes in that setting, not that normal age-related mTORC1 activity causes them, and it does not test people or intermittent activity patterns.
Abstract
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mTORC1 activity is increased in muscle with aging and is implicated as a potential driver of age-related declines in muscle health. While pharmacological inhibition of mTORC1 improves lifespan and healthspan, it remains unclear whether chronic activation of mTORC1 is sufficient to accelerate aging in skeletal muscle. We aimed to address this question using an inducible model of muscle-specific knockout of Depdc5, which encodes the protein DEP domain containing 5 (DEPDC5), a negative regulator of mTORC1.
Read the full abstract on PubMed →At a glance
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| Evidence type | A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Mouse (inducible skeletal muscle-specific Depdc5 knockout, 27-month-old male mice; dietary rapamycin arm)); the code names the system studied -- animal work can be rigorous and still not be human data. |
| Study type | 4 - Animal Study |
| Model system | Mouse (inducible skeletal muscle-specific Depdc5 knockout, 27-month-old male mice; dietary rapamycin arm) |
| Journal | Aging Cell |
| Year | 2026 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1111/acel.70805 · PMID 42992583 |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
People in the Atlas
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Graduate student in Blake Rasmussen's lab in San Antonio who studies what overactive mTORC1 in skeletal muscle does to metabolism, inflammation and exercise adaptation in aging and overnutrition
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Muscle physiologist who studies how mTORC1 and nutrient signaling control muscle growth and loss in people, including during exercise and aging.
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Co-author of two 2026 studies on constitutive mTORC1 activation in skeletal muscle from the Rasmussen laboratory.
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Co-author of two 2026 studies on constitutive mTORC1 activation in skeletal muscle from the Rasmussen laboratory.
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Co-author of two 2026 studies on constitutive mTORC1 activation in skeletal muscle from the Rasmussen laboratory.
More: 1 other author
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Biologist of aging at UT Health San Antonio whose work in this Atlas spans rapamycin in mice and in common marmosets. He is a co-author on the Interventions Testing Program reports from the San Antonio site and on the marmoset rapamycin studies on blood markers, epigenetic age and the salivary gland
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