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.

Current and future therapeutic approaches to the congenital myopathies

“…The sarcomeric thin filament is an essential component of normal muscle function, through conformational changes allowing myosin head binding to actin monomers and, ultimately, force production, prompted by Ca 2+ binding to one of its components, troponin C. To understand how NM-related mutations disrupt normal thin filament function, experimental studies have used muscle samples from NM patients or from mouse models reproducing the human condition [86,[90][91][92][93][94][95][96]. These studies have revealed that the absence of certain proteins (e.g.…”

“…Supported by preclinical data in a mouse model of ACTA1-related NM [90], a pilot study in 5 patients with NM suggested a beneficial effect of l-tyrosine, with reduced fatigue and improvement of drooling [111]. A recent report of a single case with severe KLHL40-related NM suggested a sustained beneficial response to the acetylcholinesterase inhibitor pyridostigmine [112], indicating an associated neuromuscular transmission defect potentially amenable to treatment, corresponding to observations in other congenital myopathies, in particular the CNMs (see above).…”

Sexually dimorphic myofilament function in a mouse model of nemaline myopathy

“…For instance, for the His40Tyr skeletal a-actin mutation, the most severely affected individual was a male who died at 2 months of age while the female patient is still alive at 51 years of age [6]. Similarly, in the transgenic mouse model expressing the same mutation, 60% of the males die by week 13 whereas females have a normal lifespan [7]. Even though the underlying causes of death are totally unknown, Nguyen et al [7], proposes respiratory failure as a potential contributing event.…”

“…Similarly, in the transgenic mouse model expressing the same mutation, 60% of the males die by week 13 whereas females have a normal lifespan [7]. Even though the underlying causes of death are totally unknown, Nguyen et al [7], proposes respiratory failure as a potential contributing event. Altogether, these observations suggest that this specific mutation is more potent in males than in females.…”

Insights into the effects of disease‐causing mutations in human actins

“…Using a mouse expressing the H40Y mutation, Gineste et al [2013] demonstrated, using MRI and 31 P-MRS, that this mutation resulted in impaired muscle function and altered energy metabolism. Another study, using the same mouse, demonstrated that mating this mouse to one that caused cardiac hypertrophy, or alternatively, administering oral tyrosine supplementation eased the muscle weakness caused by the H40Y mutation [Nguyen et al, 2011]. …”