L-tyrosine supplementation does not ameliorate skeletal muscle dysfunction in zebrafish and mouse models of dominant skeletal muscle \u03b1-actin nemaline myopathy

Adriana M Messineo,Robert J Bryson-Richardson,Kristen J Nowak,Christophe Vilmen,Augustin C Ogier,David Bendahan,Nigel G Laing,Tamar E Sztal,Dorothee Hahne,Charlotte Gineste,Elyshia L Mcnamara,Julien Gondin

doi:10.1038/s41598-018-29437-z

Abstract

L-tyrosine supplementation may provide benefit to nemaline myopathy (NM) patients, however previous studies are inconclusive, with no elevation of L-tyrosine levels in blood or tissue reported. We evaluated the ability of L-tyrosine treatments to improve skeletal muscle function in all three published animal models of NM caused by dominant skeletal muscle α-actin (ACTA1) mutations. Highest safe L-tyrosine concentrations were determined for dosing water and feed of wildtype zebrafish and mice respectively. NM TgACTA1D286G-eGFP zebrafish treated with 10 μM L-tyrosine from 24 hours to 6 days post fertilization displayed no improvement in swimming distance. NM TgACTA1D286G mice consuming 2% L-tyrosine supplemented feed from preconception had significant elevations in free L-tyrosine levels in sera (57%) and quadriceps muscle (45%) when examined at 6–7 weeks old. However indicators of skeletal muscle integrity (voluntary exercise, bodyweight, rotarod performance) were not improved. Additionally no benefit on the mechanical properties, energy metabolism, or atrophy of skeletal muscles of 6–7 month old TgACTA1D286G and KIActa1H40Y mice eventuated from consuming a 2% L-tyrosine supplemented diet for 4 weeks. Therefore this study yields important information on aspects of the clinical utility of L-tyrosine for ACTA1 NM.

Highlights

Tyrosine is a non-essential amino acid that serves as a precursor for several biologically active substances including the brain catecholamine neurotransmitters norepinephrine (NE) and dopamine
We tested different L-tyrosine treatment regimes on the dominant ACTA1-nemaline myopathy (NM) zebrafish and mouse models, and evaluated potential effects on skeletal muscle function using physiological assays and parameters of voluntary exercise
Whilst there was a trend between decreasing concentrations of L-tyrosine and resting heart rate, we observed a significant increase in resting heart rate for zebrafish treated with 0.1 μM and 1 μM, suggesting that L-tyrosine was eliciting a biological effect in the fish

Summary

Introduction

Tyrosine is a non-essential amino acid that serves as a precursor for several biologically active substances including the brain catecholamine neurotransmitters norepinephrine (NE) and dopamine. Dietary supplementation with L-tyrosine may have therapeutic application for patients with the skeletal muscle disorder nemaline myopathy (NM)[7,8,9]. Albeit promising data from the few patient studies and the single NM mouse model report, we aimed to comprehensively assess one aspect of the reported therapeutic benefit of dietary supplementation of L-tyrosine, skeletal muscle function. We evaluated different levels of L-tyrosine supplementation in wildtype (WT) zebrafish and mice to identify the highest safe L-tyrosine concentration to dose our NM models. We tested different L-tyrosine treatment regimes on the dominant ACTA1-NM zebrafish and mouse models, and evaluated potential effects on skeletal muscle function using physiological assays and parameters of voluntary exercise

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Conclusion