L-tyrosine supplementation does not ameliorate skeletal muscle dysfunction in zebrafish and mouse models of dominant skeletal muscle α-actin nemaline myopathy

Nemaline myopathy (NM) is a skeletal muscle disorder with no curative treatment. Although L tyrosine administration has been indicated to provide benefit to patients, previous studies have been limited due to sample size or not testing for raised L tyrosine levels. We evaluated the efficacy of L tyrosine treatment to improve skeletal muscle function in three animal models of NM caused by skeletal muscle α-actin (ACTA1) mutations. Firstly we determined the maximum safest L tyrosine concentration for inclusion in the water of wildtype zebrafish. We then treated NM TgACTA1D286G-eGFP zebrafish from 24 hours post fertilization with the highest safe L tyrosine dose (10 μM). At 6 days post fertilization, no significant improvement was detected in skeletal muscle function (swimming distance). We also determined the highest safe L tyrosine dose for dietary L tyrosine supplementation to wildtype mice. Next we treated the NM TgACTA1D286G mouse model continuously from preconception with 2% L tyrosine supplemented to regular feed. We examined skeletal muscles at 6-7 weeks using indicators of skeletal muscle integrity: bodyweight, voluntary running wheel and rotarod performance, all parameters previously shown to be reduced in TgACTA1D286G mice. The L tyrosine treatment regime did not result in any improvement of these parameters, despite significant elevation of free L tyrosine levels in sera (57%) and quadriceps muscle (45%) of treated TgACTA1D286G mice. Additionally, we assessed the effects of 4 weeks of 2% L tyrosine dietary supplementation on skeletal muscle function of older (6-7 month old) NM TgACTA1D286G and KIActa1H40Y mice. This dosing regime did not improve decreased bodyweight, nor the mechanical properties, energy metabolism, or atrophy of skeletal muscles in these NM models. Together these findings demonstrate that with the treatment regimes and doses evaluated, L tyrosine does not therapeutically modulate dysfunctional skeletal muscles in NM animal models with dominant ACTA1 mutations. Therefore this study yields important information on aspects of the clinical utility of L tyrosine for ACTA1 NM.