Skeletal Muscle Involvement in Friedreich Ataxia and Potential Effects of Recombinant Human Erythropoietin Administration on Muscle Regeneration and Neovascularization
ABSTRACT Friedreich ataxia (FRDA) is caused by reduced expression of the mitochondrial protein frataxin. Cardiac muscle involvement has been attributed to mitochondrial dysfunction, but involvement of skeletal muscle has not been fully investigated. Improved motor skills in FRDA patients after administration of recombinant human erythropoietin (rhuEPO) have been reported. To elucidate the characteristics of skeletal muscle in FRDA and assess the potential effects of rhuEPO on skeletal muscle neovascularization and regeneration, 7 genetically confirmed FRDA patients underwent biopsy of the gastrocnemius muscle before and after administration of 3,000 international units of rhuEPO 3 times per week for 2 months. Muscle tissue was investigated using standard histologic methods, immunohistochemistry, and biochemical assays of mitochondrial enzymes. In pretreatment FRDA samples, there were neurogenic and myopathic changes and reduced capillary density versus that in healthy control biopsies (n = 4). Satellite cells were increased, but markers of satellite cell activation and differentiation did not differ from controls. Respiratory chain complex and citrate synthase activities were reduced in FRDA and remained unchanged after treatment. Administration of rhuEPO resulted in increases in muscle capillary densities and in endothelial progenitor cells in peripheral blood. These data indicate that there are morphological and biochemical abnormalities of skeletal muscle in FRDA. The rhuEPO-induced changes were subtle, but increased capillary density might result in improved oxygen supply and myofiber function.
SourceAvailable from: Sylvia Boesch[Show abstract] [Hide abstract]
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. EU Clinical Trials Register2008-000040-13.PLoS ONE 07/2013; 8(7):e69229. DOI:10.1371/journal.pone.0069229 · 3.53 Impact Factor
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ABSTRACT: Erythropoietin (Epo) has been thought to act exclusively on erythroid progenitor cells. The identification of Epo receptor (EpoR) in non-haematopoietic cells and tissues including neurons, astrocytes, microglia, immune cells, cancer cell lines, endothelial cells, bone marrow stromal cells, as well as cells of myocardium, reproductive system, gastrointestinal tract, kidney, pancreas and skeletal muscle indicates that Epo has pleiotropic actions. Epo shows signals through protein kinases, anti-apoptotic proteins and transcription factors. In light of interest of administering recombinant human erythropoietin (rhEpo) and its analogues for limiting infarct size and left ventricular (LV) remodelling after acute myocardial infarction (AMI) in humans, the foremost studies utilising rhEpo are reviewed. The putative mechanisms involved in Epo-induced cardioprotection are related to the antiapoptotic, anti-inflammatory and angiogenic effects of Epo. Thus, cardioprotective potentials of rhEpo are reviewed in this article by focusing on clinical applicability. An overview of non-haematopoietic Epo analogues, which are a reliable alternative to the classic EpoR agonists and may prevent undesired side effects, is also provided.International journal of cardiology 12/2013; 171(2). DOI:10.1016/j.ijcard.2013.12.011 · 6.18 Impact Factor
Article: Erythropoietin in Friedreich ataxia[Show abstract] [Hide abstract]
ABSTRACT: In Friedreich ataxia (FRDA), several candidate substances including erythropoietin (EPO) focus on increase in the amount of frataxin and aim to counteract the consequences of frataxin deficiency. Evidence for recombinant human erythropoietin (rHuEPO) in FRDA is based on in vitro studies using mouse neuronal cell lines, human fibroblasts, cardiomyocytes, and primary lymphocytes from FRDA patients or control subjects which showed a dose-dependent increase of frataxin after incubation with different erythropoietins. The mechanism by which EPO induces frataxin increase remains to be elucidated, but may involve post-transcriptional and/or post-translational modifications of frataxin or alterations in frataxin half-life and metabolism. In vivo data on rHuEPO's ability to increase frataxin in FRDA patients is contradictory as studies on the effect of EPO derivatives in FRDA differ in treatment regimen, sample size, and duration. Open-label studies indicate for sustained frataxin increase, decrease of oxidative stress, and clinical improvement in FRDA patients after administration of rHuEPO. Two randomized controlled studies found acceptable safety and tolerability of EPO derivatives in FRDA. Secondary outcome measures, however, such as frataxin up-regulation and clinical efficacy were not met. This review will focus on (i) pre-clinical work on erythropoietins in FRDA and (ii) clinical studies in FRDA patients exposed to erythropoietins.Journal of Neurochemistry 08/2013; 126(Supp.1):80-7. DOI:10.1111/jnc.12301 · 4.24 Impact Factor