Nemaline myopathy, the most common congenital
myopathy, is caused by mutations in genes encoding thin filament and thin filament-associated
proteins in skeletal muscles. Severely affected patients fail to survive beyond the first year of life due to severe
muscle weakness. There are no specific
therapies to combat this
muscle weakness. We have generated the first knock-in mouse model for severe
nemaline myopathy by replacing a normal allele of the α-skeletal actin gene with a mutated form (H40Y), which causes severe
nemaline myopathy in humans. The Acta1(H40Y) mouse has severe
muscle weakness manifested as shortened lifespan, significant forearm and isolated
muscle weakness and decreased mobility. Muscle pathologies present in the human patients (e.g. nemaline rods, fibre
atrophy and increase in slow fibres) were detected in the Acta1(H40Y) mouse, indicating that it is an excellent model for severe
nemaline myopathy. Mating of the Acta1(H40Y) mouse with hypertrophic four and a half LIM domains protein 1 and
insulin-like growth factor-1 transgenic mice models increased forearm strength and mobility, and decreased nemaline pathologies. Dietary
L-tyrosine supplements also alleviated the mobility deficit and decreased the chronic repair and nemaline rod pathologies. These results suggest that
L-tyrosine may be an effective treatment for
muscle weakness and immobility in
nemaline myopathy.