Bioenergetics of the Calf Muscle in Friedreich Ataxia Patients Measured by 31P-MRS Before and After Treatment with Recombinant Human Erythropoietin

Wolfgang Nachbauer,Sylvia Boesch,Rainer Schneider,Michael Schocke,Andreas Eigentler,Werner Poewe,Julia Wanschitz,Annalisa Pastore

doi:10.1371/journal.pone.0069229

Wolfgang Nachbauer, Sylvia Boesch + Show 6 more

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https://doi.org/10.1371/journal.pone.0069229

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Abstract

Friedreich ataxia (FRDA) is caused by a GAA repeat expansion in the FXN gene leading to reduced expression of the mitochondrial protein frataxin. Recombinant human erythropoietin (rhuEPO) is suggested to increase frataxin levels, alter mitochondrial function and improve clinical scores in FRDA patients. Aim of the present pilot study was to investigate mitochondrial metabolism of skeletal muscle tissue in FRDA patients and examine effects of rhuEPO administration by phosphorus 31 magnetic resonance spectroscopy (31P MRS). Seven genetically confirmed FRDA patients underwent 31P MRS of the calf muscles using a rest-exercise-recovery protocol before and after receiving 3000 IU of rhuEPO for eight weeks. FRDA patients showed more rapid phosphocreatine (PCr) depletion and increased accumulation of inorganic phosphate (Pi) during incremental exercise as compared to controls. After maximal exhaustive exercise prolonged regeneration of PCR and slowed decline in Pi can be seen in FRDA. PCr regeneration as hallmark of mitochondrial ATP production revealed correlation to activity of complex II/III of the respiratory chain and to demographic values. PCr and Pi kinetics were not influenced by rhuEPO administration. Our results confirm mitochondrial dysfunction and exercise intolerance due to impaired oxidative phosphorylation in skeletal muscle tissue of FRDA patients. MRS did not show improved mitochondrial bioenergetics after eight weeks of rhuEPO exposition in skeletal muscle tissue of FRDA patients.Trial Registration EU Clinical Trials Register 2008-000040-13

Highlights

Friedreich Ataxia (FRDA) is the most common inherited ataxia among Caucasian populations
Pi increased in both groups (FRDA: 11.6564.43, controls: 12.9761.58; p = 0.837), while PCr levels declined in parallel (FRDA: 22.8968.36, controls: 18.5163.03; p = 0.205)
In this study we investigated the oxidative energy metabolism of the calf muscles in FRDA patients by 31 magnetic resonance spectroscopy (31P magnetic resonance spectroscopy (MRS)) using a restexercise-recovery protocol

Summary

Introduction

Friedreich Ataxia (FRDA) is the most common inherited ataxia among Caucasian populations. Muscle tissue especially cardiac muscle and skeletal muscle show decreased frataxin expression and impairment of the respiratory chain [7,8]. Reduced skeletal muscle adenosine triphosphate (ATP) production and mitochondrial dysfunction could be demonstrated earlier by magnetic resonance spectroscopy (MRS) [9,10]. Decrease in oxidative stress [15] and changes in mitochondrial function [16] have been reported after rhuEPO application in FRDA. Phosphorus 31 magnetic resonance spectroscopy (31P MRS) offers a non invasive investigation of human skeletal muscle bioenergetics by monitoring relative and absolute changes of phosphocreatine (PCr), inorganic phosphate (Pi) and adenosine triphosphate (ATP) during incremental exercise and recovery [17]. Investigate mitochondrial function of skeletal muscle tissue in FRDA patients and to examine effects of rhuEPO application

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