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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies

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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
[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

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 type: Scholarships abroad - Research