What question did this study set out to answer?

The study aims to investigate the effects of rapamycin on mTORC1-mediated angiogenic gene expression in aged skeletal muscle.

May 14, 2026

Rapamycin Reverses mTORC1-Driven Suppression of Angiogenic Gene Expression in Aged Mouse Skeletal Muscle

Key Points

The study aims to investigate the effects of rapamycin on mTORC1-mediated angiogenic gene expression in aged skeletal muscle.
Used conditional knockout of DEPDC5 in aged mice (27 months old) to evaluate mTORC1 activity and gene expression changes.
Measured phosphorylation levels of S6 Ribosomal Protein and assessed transcriptional pathways related to inflammation and angiogenesis after rapamycin treatment.
Compared gene expression between DEPDC5 knockout and wild-type mice before and after rapamycin administration.
In DEPDC5 KO mice, mTORC1 was hyperactivated, indicated by higher phosphorylation of S6 Ribosomal Protein (S235/236).
Rapamycin treatment partially reversed angiogenesis-related transcriptional pathway reductions but did not significantly alter inflammation-related gene expression.
Increased expression of some inflammation-related genes and TNF protein was observed in KO mice compared to WT, with rapamycin showing no clear effect on these.

Abstract

In skeletal muscle, mTORC1 (Mechanistic Target of Rapamycin Complex 1) is activated acutely by exercise and by amino acid ingestion. However, as individuals age, basal mTORC1 activity increases, altering proper anabolic and catabolic signaling. These age-related changes are implicated in various pathologies, including muscle atrophy and insulin resistance. We observed that hyperactive signaling through mTORC1 in skeletal muscle via conditional knockout (KO) of an upstream inhibitor, DEPDC5 (DEP Domain Containing 5), significantly alters the muscle transcriptome, upregulating pathways related to the cell cycle and monocyte chemotaxis, and decreasing pathways related to angiogenesis and fatty acid metabolism. This led us to hypothesize that DEPDC5 KO would exacerbate inflammation and immune cell infiltration and reduce angiogenesis in aged mice, and that these changes would be reversed by rapamycin treatment. In 27-month-old mice, we observed hyperactivation of mTORC1 in DEPDC5 KO mice compared to wild-type (WT), indicated by increased phosphorylation of S6 Ribosomal Protein (S235/236) and altered autophagy markers. These mTORC1-driven signaling effects were partially reversed by rapamycin treatment. DEPDC5 KO increased the expression of some inflammation-related genes, and of TNF protein compared to WT but did not increase IL-6 protein expression. There was no clear reversal of inflammation-related genes or TNF protein with rapamycin treatment. Angiogenesis-related transcriptional pathways were reduced in KO compared to WT, which were reversed by rapamycin administration. These results indicate that mTORC1 hyperactivation may be a driver of muscle inflammation and reduced angiogenesis, and that rapamycin can reverse some of these changes. Future work will determine if these transcriptional changes coincide with altered capillary density and immune cell infiltration in aged skeletal muscle. Supported by NIH P30AG013319 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Mark Helpful

Bookmark

Relay