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| Status |
Public on Apr 30, 2024 |
| Title |
Sarm1 knockout prevents type 1 diabetic bone disease in females independent of neuropathy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Diabetic patients have a high risk of developing skeletal diseases accompanied by diabetic peripheral neuropathy (DPN). In this study, we isolated the role of DPN in skeletal disease with global and conditional knockout models of sterile-α and TIR-motif-containing protein-1 (Sarm1). SARM1, an NADase highly expressed in the nervous system, regulates axon degeneration upon a range of insults, including DPN. Global knockout of Sarm1 prevented DPN, but not skeletal disease, in male mice with type 1 diabetes (T1D). Female wild type mice also developed diabetic bone disease, but without DPN. Unexpectedly, global Sarm1 knockout completely protected female mice from T1D-associated bone suppression and skeletal fragility despite comparable muscle atrophy and hyperglycemia. Global Sarm1 knockout rescued bone health through sustained osteoblast function with abrogation of local oxidative stress responses. This was independent of the neural actions of SARM1, as beneficial effects on bone were lost with neural conditional Sarm1 knockout. This study demonstrates that the onset of skeletal disease occurs rapidly in both male and female mice with T1D completely independent of DPN. In addition, this reveals that clinical SARM1 inhibitors, currently being developed for treatment of neuropathy, may also have benefits for diabetic bone through actions outside of the nervous system.
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| Overall design |
RNAseq was performed using RNA extracted from marrow-depleted femur and tibia bones harvested from wild type (WT) and global Sarm1 knockout (Sarm1-KO) female mice at 11-weeks of age. Mice were further categorized by the presence or absence of streptozotocin induced type 1 diabetes, induced 3-weeks prior at the age of 8-weeks (four groups total: WT non-diabetic, Sarm1-KO non-diabetic, WT T1D, Sarm1-KO T1D). The 3-week time point was selected to capture gene changes early in the course of disease, around the time that changes in bone by microCT were beginning to emerge.
>>>Submitter states that raw data are not available due to file loss<<<
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| Contributor(s) |
Brazill JM, Shen IR, Craft C, Magee KL, Park JS, Lorenz M, Strickland A, Wee NK, Zhang X, Beeve AT, Meyer GA, Milbrandt J, DiAntonio A, Scheller EL |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Dec 30, 2023 |
| Last update date |
Apr 30, 2024 |
| Contact name |
Erica L Scheller |
| Organization name |
Washington University
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| Street address |
660 S Euclid Ave
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| City |
Saint Louis |
| State/province |
MO |
| ZIP/Postal code |
63110 |
| Country |
USA |
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| Platforms (1) |
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| Samples (23)
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| Relations |
| BioProject |
PRJNA1059265 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE252292_TPM_values.txt.gz |
1.4 Mb |
(ftp)(http) |
TXT |
| GSE252292_read_counts.txt.gz |
708.9 Kb |
(ftp)(http) |
TXT |
| Raw data not provided for this record |
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