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

Area of Science:

• Muscle Biology
• Molecular Genetics
• Protein Quality Control

Background:

• Limb-girdle muscular dystrophy 1D (LGMD1D) is a rare genetic disorder affecting skeletal muscle.
• The DNAJB6 gene, encoding a heat shock protein, plays a role in muscle function and disease.

Purpose of the Study:

• To elucidate the function of DNAJB6 in skeletal muscle.
• To identify potential therapeutic targets for LGMD1D.

Main Methods:

• Generated DNAJB6 knockout myoblasts using CRISPR/Cas9.
• Utilized mass spectrometry to identify protein changes in knockout myoblasts.
• Analyzed muscle tissue from wild-type and mutant mice, assessing muscle histochemistry, protein levels, and functional strength.

Main Results:

• DNAJB6 inactivation resulted in sarcomeric protein accumulation and hypertrophic myotubes with increased fusion.
• Reduced glycogen synthase kinase-β (GSK3β) activity was observed in DNAJB6 knockout myotubes.
• LGMD1D-associated DNAJB6 mutations increased GSK3β activity, suppressing key myogenic signaling pathways (β-catenin, NFAT3c).
• Lithium chloride treatment, a GSK3β inhibitor, improved muscle size and strength in a preclinical LGMD1D mouse model.

Conclusions:

• DNAJB6 is essential for protein quality control and negatively regulates myogenic signaling in skeletal muscle.
• LGMD1D mutations disrupt myogenic signaling via enhanced GSK3β activity.
• GSK3β inhibition presents a potential therapeutic strategy for LGMD1D.