| Full text | |
| Author(s): |
Ortiz-Cordero, Carolina
[1, 2]
;
Bincoletto, Claudia
[1, 3]
;
Dhoke, Neha R.
[1]
;
Selvaraj, Sridhar
[1]
;
Magli, Alessandro
[1]
;
Zhou, Haowen
[4]
;
Kim, Do-Hyung
[5]
;
Bang, Anne G.
[4]
;
Perlingeiro, Rita C. R.
[1, 2]
Total Authors: 9
|
| Affiliation: | [1] Univ Minnesota, Lillehei Heart Inst, Dept Med, 4-128 CCRB, 2231 6th St SE, Minneapolis, MN 55455 - USA
[2] Univ Minnesota, Dept Integrat Biol & Physiol, Minneapolis, MN 55455 - USA
[3] Univ Fed Sao Paulo UNIFESP, Dept Farmacol, Escola Paulista Med EPM, Sao Paulo - Brazil
[4] Sanford Burnham Prebys Med Discovery Inst, Conrad Prebys Ctr Chem Genom, La Jolla, CA - USA
[5] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN - USA
Total Affiliations: 5
|
| Document type: | Journal article |
| Source: | STEM CELL REPORTS; v. 16, n. 11, p. 2752-2767, NOV 9 2021. |
| Web of Science Citations: | 1 |
| Abstract | |
Fukutin-related protein (FKRP) is a glycosyltransferase involved in glycosylation of alpha-dystroglycan (cc-DG). Mutations in FKRP are associated with muscular dystrophies (MD) ranging from limb-girdle LGMDR9 to Walker-Warburg Syndrome (WWS), a severe type of congenital MD. Although hypoglycosylation of cc-DG is the main hallmark of this group of diseases, a full understanding of the underlying pathophysiology is still missing. Here, we investigated molecular mechanisms impaired by FKRP mutations in pluripotent stem (PS) cell-derived myotubes. FKRP-deficient myotubes show transcriptome alterations in genes involved in extracellular matrix receptor interactions, calcium signaling, PI3K-Akt pathway, and lysosomal function. Accordingly, using a panel of patient-specific LGMDR9 and WWS induced PS cell-derived myotubes, we found a significant reduction in the autophagy-lysosome pathway for both disease phenotypes. In addition, we show that WWS myotubes display decreased ERK1/2 activity and increased apoptosis, which were restored in gene edited myotubes. Our results suggest the autophagy-lysosome pathway and apoptosis may contribute to the FKRP-associated MD pathogenesis. (AU) | |
| FAPESP's process: | 18/07633-2 - Induced pluripotent stem cells as a tool for pharmacological and toxicological studies: a potential role of autophagy in sarcopenia |
| Grantee: | Claudia Bincoletto Trindade |
| Support Opportunities: | Scholarships abroad - Research |