title: Hypertrophy and dietary tyrosine ameliorate the phenotypes of a mouse model of severe nemaline myopathy.
abstract: 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.
authors: Neuromuscular and Regenerative Medicine Unit, School of Medical Sciences, University of New South Wales, Kensington, NSW 2052, Australia.
authors: Mai-Anh T
authors: MA
authors: Nguyen
authors: Josephine E
authors: JE
authors: Joya
authors: Anthony J
authors: AJ
authors: Kee
authors: Ana
authors: A
authors: Domazetovska
authors: Nan
authors: N
authors: Yang
authors: Jeff W
authors: JW
authors: Hook
authors: Frances A
authors: FA
authors: Lemckert
authors: Emma
authors: E
authors: Kettle
authors: Valentina A
authors: VA
authors: Valova
authors: Philip J
authors: PJ
authors: Robinson
authors: Kathryn N
authors: KN
authors: North
authors: Peter W
authors: PW
authors: Gunning
authors: Christina A
authors: CA
authors: Mitchell
authors: Edna C
authors: EC
authors: Hardeman
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018737:Hand Strength; D006984:Hypertrophy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000235:genetics; D018908:Muscle Weakness / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology*; D009154:Mutation; D017696:Myopathies, Nemaline / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D014443:Tyrosine / Q000627:therapeutic use*
chemical_list: D014443:Tyrosine