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Publication : Mechanisms of skeletal muscle wasting in a mouse model for myotonic dystrophy type 1.

First Author  Morriss GR Year  2018
Journal  Hum Mol Genet Volume  27
Issue  16 Pages  2789-2804
PubMed ID  29771332 Mgi Jnum  J:264569
Mgi Id  MGI:6194477 Doi  10.1093/hmg/ddy192
Citation  Morriss GR, et al. (2018) Mechanisms of skeletal muscle wasting in a mouse model for myotonic dystrophy type 1. Hum Mol Genet 27(16):2789-2804
abstractText  Myotonic dystrophy type 1 (DM1) is a multi-systemic disease resulting in severe muscle weakening and wasting. DM1 is caused by expansion of CTG repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. We have developed an inducible, skeletal muscle-specific mouse model of DM1 (CUG960) that expresses 960 CUG repeat-expressing animals (CUG960) in the context of human DMPK exons 11-15. CUG960 RNA-expressing mice induced at postnatal day 1, as well as adult-onset animals, show clear, measurable muscle wasting accompanied by severe histological defects including central myonuclei, reduced fiber cross-sectional area, increased percentage of oxidative myofibers, the presence of nuclear RNA foci that colocalize with Mbnl1 protein, and increased Celf1 protein in severely affected muscles. Importantly, muscle loss, histological abnormalities and RNA foci are reversible, demonstrating recovery upon removal of toxic RNA. RNA-seq and protein array analysis indicate that the balance between anabolic and catabolic pathways that normally regulate muscle mass may be disrupted by deregulation of platelet derived growth factor receptor beta signaling and the PI3K/AKT pathways, along with prolonged activation of AMP-activated protein kinase alpha signaling. Similar changes were detected in DM1 skeletal muscle compared with unaffected controls. The mouse model presented in this paper shows progressive skeletal muscle wasting and has been used to identify potential molecular mechanisms underlying skeletal muscle loss. The reversibility of the phenotype establishes a baseline response for testing therapeutic approaches.
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