Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb

Area of Science:

• Muscle physiology and genetics
• Protein aggregation diseases
• Skeletal muscle biology

Background:

• Ariel mouse mutant exhibits rapid skeletal muscle myofibrillar degeneration and hindlimb paralysis.
• The disease is caused by a mutation (L342Q) in the skeletal muscle myosin MYH4 (MyHC IIb) gene.
• The mutated myosin protein is prone to forming large intracellular aggregates.

Purpose of the Study:

• To investigate the molecular mechanisms underlying myofibrillar degeneration in the Ariel mouse model.
• To explore the pathogenic pathway of protein aggregate formation in skeletal muscle.
• To assess the therapeutic potential of eliminating the mutant protein.

Main Methods:

• Genetic analysis of the Ariel mouse mutation.
• Biochemical analysis of purified protein aggregates.
• Histological examination of skeletal muscle.
• Functional assessment of muscle fibers from heterozygous and homozygous mice.

Main Results:

• The L342Q mutation in MYH4 causes rapid protein aggregation and skeletal muscle degeneration in homozygous mice.
• Aggregates contain proteins commonly found in human myofibrillar myopathies, suggesting a conserved disease pathway.
• Heterozygous mice show reduced levels of mutant MYH4 and are phenotypically normal, with a slight increase in muscle force.
• The human MYH1 protein with the equivalent mutation is also more prone to aggregation.

Conclusions:

• The Ariel mouse model recapitulates key features of human myofibrillar myopathies.
• Myosin aggregation is a central pathogenic event in this skeletal muscle disease.
• Reducing mutant protein levels can prevent disease progression, offering potential therapeutic insights.