Skeletal Muscle Involvement in Friedreich Ataxia and Potential Effects of Recombinant Human Erythropoietin Administration on Muscle Regeneration and Neovascularization

Departments of Neurology, Medical University Innsbruck, Innsbruck, Austria.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 07/2012; 71(8):708-15. DOI: 10.1097/NEN.0b013e31825fed76
Source: PubMed


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.

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    • "When comparing muscle tissue prior to treatment, Nachbauer et al. [125] confirmed that rhEpo increased capillary densities and endothelial progenitor cells in blood, and suggested that the new vascularisation produced by rhEpo may improve muscle function in FRDA patients. If rhEpo or its analogues improve(s) the muscle and mitochondrial function it would help improve the cardiac function. "
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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 · 4.04 Impact Factor
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    • "However, in line with previous results in rodents (Cayla et al., 2008; Hojman et al., 2009), 8 weeks of EPO treatment enhanced skeletal muscle mitochondrial oxidative phosphorylation and maximal electron transport capacity (Plenge et al., 2012). Interestingly, prolonged EPO administration increased muscle capillary density in Friedreich Ataxia patients and may therefore contribute to the improved motor function reported following EPO treatment (Nachbauer et al., 2012). Altogether, these findings suggest that in skeletal muscle in vivo, EPO may not activate the EPO-R or the established EPO signaling cascades, such as JAK2/STAT5 or PI3-K/Akt. "
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    ABSTRACT: Erythropoietin (EPO) primarily activates erythroid cell proliferation and growth and is active in several types of non-hematopoietic cells via its interaction with the EPO-receptor (EPO-R). This review focuses on the role of EPO in skeletal muscle. The EPO-R is expressed in skeletal muscle cells and EPO may promote myoblast differentiation and survival via the activation of the same signaling cascades as in hematopoietic cells, such as STAT5, MAPK and Akt. Inconsistent results exist with respect to the detection of the EPO-R mRNA and protein in muscle cells, tissue and across species and the use of non-specific EPO-R antibodies contributes to this problem. Additionally, the inability to reproducibly detect an activation of the known EPO-induced signaling pathways in skeletal muscle questions the functionality of the EPO-R in muscle in vivo. These equivocal findings make it difficult to distinguish between a direct effect of EPO on skeletal muscle, via the activation of its receptor, and an indirect effect resulting from a better oxygen supply to the muscle. Consequently, the precise role of EPO in skeletal muscle and its regulatory mechanism/s remain to be elucidated. Further studies are required to comprehensively establish the importance of EPO and its function in skeletal muscle health.
    Frontiers in Physiology 07/2013; 4:176. DOI:10.3389/fphys.2013.00176 · 3.53 Impact Factor
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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. EU Clinical Trials Register2008-000040-13.
    PLoS ONE 07/2013; 8(7):e69229. DOI:10.1371/journal.pone.0069229 · 3.23 Impact Factor
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