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Lithium chloride corrects weakness and myopathology in a preclinical model of LGMD1D. | LitMetric

Lithium chloride corrects weakness and myopathology in a preclinical model of LGMD1D.

Neurol Genet

Washington University School of Medicine (A.R.F., R.B., S.K.P., H.L.T., C.C.W); Department of Neurology (A.R.F., R.B., S.K.P., C.C.W), Hope Center for Neurological Diseases, St. Louis, MO; Harbor-UCLA Medical Center (T.-F.C.), Department of Pediatrics, Division of Medical Genetics, Torrance, CA; Department of Cell Biology and Physiology (H.L.T.), Saint Louis, MO.

Published: April 2019

Objective: To understand DNAJB6's function in skeletal muscle and identify therapeutic targets for limb-girdle muscular dystrophy 1D (LGMD1D).

Methods: DNAJB6 knockout (KO) myoblasts were generated with Crispr/cas9 technology, and differentially accumulated proteins were identified using stable isotope labeling, followed by quantitative mass spectrometry. Cultured KO myotubes and mouse muscle from DNAJB6b-WT or DNAJB6b-F93L mice were analyzed using histochemistry, immunohistochemistry, and immunoblot. Mouse functional strength measures included forelimb grip strength and inverted wire hang.

Results: DNAJB6 inactivation leads to the accumulation of sarcomeric proteins and hypertrophic myotubes with an enhanced fusion index. The increased fusion in DNAJB6 KO myotubes correlates with diminished glycogen synthase kinase-β (GSK3β) activity. In contrast, LGMD1D mutations in enhance GSK3β activation and suppress β-catenin and NFAT3c signaling. GSK3β inhibition with lithium chloride improves muscle size and strength in an LGMD1D preclinical mouse model.

Conclusions: Our results suggest that DNAJB6 facilitates protein quality control and negatively regulates myogenic signaling. In addition, LGMD1D-associated mutations inhibit myogenic signaling through augmented GSK3β activity. GSK3β inhibition with lithium chloride may be a therapeutic option in LGMD1D.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510529PMC
http://dx.doi.org/10.1212/NXG.0000000000000318DOI Listing

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