Prolonged erythropoietin treatment does not impact gene expression in human skeletal muscle

Christensen, Britt; Nellemann, Birgitte; Thorsen, Kasper; Nielsen, Morten Muhlig; Pedersen, Steen B.; Ørnstrup, Marie Juul; Jørgensen, Jens Otto Lunde; Jessen, Niels

doi:10.1002/mus.24355

Cited by 9 publications

(14 citation statements)

References 30 publications

(117 reference statements)

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“…Furthermore, phosphorylation of ERK42/44, p38MAPK, and PPARγ in preadipocytes does not depend on Epo-R expression under normal culture conditions, but during adipocyte differentiation the expression of Epo-R increases in concomitance with increased phosphorylation of ERK42/44, p38MAPK, PPARγ, Akt, and STAT5 [2,19]. In our human study, we detected higher Epo-R mRNA levels in WAT than in bone marrow and than previously found in human skeletal muscle [13]. However, we were not able to measure any Epo-R Fig.…”

Section: Epo-r Mrna and Protein And Activation Of Signaling Pathways supporting

confidence: 54%

“…One explanation could be an increase in resting energy expenditure including fat oxidation [2], but only the former has been documented in healthy human subjects [6,7]. As regards direct peripheral actions of Epo, there is no evidence to support such effects in human skeletal muscle [12,13]. The effect of Epo treatment on WAT in humans has so far not been evaluated, but Epo-R protein and mRNA has been detected in WAT from mice in addition to a suppressive effect of Epo on fat accumulation and preadipocyte differentiation and expansion in vitro [2,14].…”

Section: Introductionmentioning

confidence: 99%

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Growth Hormone and Insulin Signaling in Acromegaly: Impact of Surgery Versus Somatostatin Analog Treatment

Dal

Høyer

Pedersen

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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Background: Erythropoietin (Epo) exerts direct effects on white adipose tissue (WAT) in mice in addition to its erythropoietic effects, and in humans Epo increases resting energy expenditure and affect serum lipid levels, but direct effects of Epo in human WAT have not been documented. We therefore investigated the effects of acute and prolonged Epo exposure on human WAT in vivo. Method: Data were obtained from two clinical trials: 1) acute Epo exposure (rHuEpo, 400 IU/kg) followed by WAT biopsies after 1 h and 2) 10 weeks treatment with the erythropoiesis-stimulating agent (ESA) Darbepoietin-alpha. Biopsies were analyzed by PCR for Epo receptor (Epo-R) mRNA. A new and highly specific antibody (A82, Amgen) was used to evaluate the presence of Epo-R by western blot analysis in addition to Epo-R signaling proteins (Akt, STAT5, p70s6k, LYN, and p38MAPK), activation of lipolytic pathways (ATGL, HSL, CGI-58, G0S2, Perilipin, Cidea, Cidec, AMPK, and ACC), and mitochondrial biogenesis (VDAC, HSP90, PDH, and SDHA). Results: No evidence of in vivo activation of the Epo-R in WAT could be documented despite detectable levels of Epo-R mRNA.Conclusion: Thus, in contradiction to animal studies, Epo treatment within a physiological relevant range in humans does not exert direct effects in a subcutaneous WAT.

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Section: Epo-r Mrna and Protein And Activation Of Signaling Pathways supporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Growth Hormone and Insulin Signaling in Acromegaly: Impact of Surgery Versus Somatostatin Analog Treatment

Dal

Høyer

Pedersen

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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“…As no studies have been able to produce unambiguous evidence, the exact connection between Epo and the alleged oxidative adaptations still remains elusive. Moreover, a recently developed sensitive antibody indicates an absence of Epo-R protein expression in skeletal muscle (Christensen et al 2014). In line with this, a recent study concludes that even though they were able to detect Epo-R mRNA in human primary skeletal muscle cells, treatment with Epo did not influence myogenesis (Lamon et al 2014).…”

Section: Comparative Effects Of Epo and Training On Skeletal Muscle Tmentioning

confidence: 79%

“…Moreover, a recently developed sensitive antibody indicates an absence of Epo‐R protein expression in skeletal muscle (Christensen et al . ). In line with this, a recent study concludes that even though they were able to detect Epo‐R mRNA in human primary skeletal muscle cells, treatment with Epo did not influence myogenesis (Lamon et al .…”

Section: Discussionmentioning

confidence: 97%

Erythropoietin administration alone or in combination with endurance training affects neither skeletal muscle morphology nor angiogenesis in healthy young men

Larsen

Vissing

Thams

et al. 2014

Experimental Physiology

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New Findings r What is the central question of this study?Is an erythropoiesis-stimulating agent (ESA), alone or in combination with endurance training, able to induce changes in human skeletal muscle fibre and vascular morphology? r What is the main finding and its importance?Human skeletal muscle morphology and angiogenetic effects did not exhibit sensitivity to ESA treatment alone. Endurance training stimulates angiogenesis and fibre type transition in the direction of a more oxidative fibre phenotype; however, addition of ESA had no further effect.The aim was to investigate the ability of an erythropoiesis-stimulating agent (ESA), alone or in combination with endurance training, to induce changes in human skeletal muscle fibre and vascular morphology. In a comparative study, 36 healthy untrained men were randomly dispersed into the following four groups: sedentary-placebo (SP, n = 9); sedentary-ESA (SE, n = 9); training-placebo (TP, n = 10); or training-ESA (TE, n = 8). The ESA or placebo was injected once weekly. Training consisted of progressive bicycling three times per week for 10 weeks. Before and after the intervention period, muscle biopsies and magnetic resonance images were collected from the thigh muscles, blood was collected, body composition measured and endurance exercise performance evaluated. The ESA treatment (SE and TE) led to elevated haematocrit, and both ESA treatment and training (SE, TP and TE) increased maximal O 2 uptake. With regard to skeletal muscle morphology, TP alone exhibited increases in whole-muscle cross-sectional area and fibre diameter of all fibre types. Also exclusively for TP was an increase in type IIa fibres and a corresponding decrease in type IIx fibres. Furthermore, an overall training effect (TP and TE) was statistically demonstrated in whole-muscle cross-sectional area, muscle fibre diameter and type IIa and type IIx fibre distribution. With regard to muscle vascular morphology, TP and TE both promoted a rise in capillary to muscle fibre ratio, with no differences between the two groups. There were no effects of ESA treatment on any of the muscle morphological parameters. Despite the haematopoietic effects of ESA, we provide novel evidence that endurance training rather than ESA treatment induces adaptational changes in angiogenesis and muscle morphology.

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“…The study was approved by the Local Ethical Committee of Central Denmark Region (M-20110035), and is registered at www.clinicaltrials.gov (NCT01320449). A detailed description of the study design and data regarding skeletal muscle and metabolic effects of ESA treatment and aerobic training has been published [6,7,16,23].…”

Section: Participantsmentioning

confidence: 99%

Comparative Effects of Aerobic Training and Erythropoietin on Oxygen Uptake in Untrained Humans

Sieljacks

Thams

Nellemann

et al. 2016

Journal of Strength and Conditioning Research

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Sieljacks, P, Thams, L, Nellemann, B, Larsen, MS, Vissing, K, and Christensen, B. Comparative effects of aerobic training and erythropoietin on oxygen uptake in untrained humans. J Strength Cond Res 30(8): 2307-2317, 2016-The present study examines responses to 10 weeks of aerobic training and/or erythropoiesis-stimulating agent (ESA) treatment on maximal oxygen uptake (V[Combining Dot Above]O2max). Thirty-six healthy, untrained men were randomly assigned to sedentary-placebo (n = 9), sedentary-ESA (SE) (n = 9), training-placebo (TP) (n = 10), or training-ESA (TE) (n = 8). The participants were treated subcutaneously once weekly with ESA (darbepoietin-α, week 1-3; 40 μg and week 4-10; 20 μg) or a placebo for 10 weeks. The training consisted of supervised cycling 3 times per week for 1 hour at an average of 65% of maximal watt, with a progressive overload during the intervention period. V[Combining Dot Above]O2max, wattmax, and hematological values were measured throughout the study. In addition, the total training workload and estimated energy consumption were recorded after each training session. ESA treatment increased hemoglobin (∼11 and ∼14%, p < 0.001) and hematocrit (∼12 and ∼13%, p < 0.001) in the SE and TE groups, respectively. The relative (but not absolute) increases in V[Combining Dot Above]O2max were more pronounced (p < 0.01) in TE (27 ± 6%), compared with SE (15 ± 4%) but not TP (19 ± 4%), indicating that training is superior to ESA in stimulating V[Combining Dot Above]O2max in untrained men. The increased oxygen uptake in the TE group did not result in higher absolute training workloads than in the TP group. In untrained men, training exhibits a greater stimulus for improvements in V[Combining Dot Above]O2max than ESA treatment, without pronounced additive effects, which is supported by similar average training workloads and energy consumption in TP and TE. Thus, in untrained men, training alone seems sufficient to induce improvement in V[Combining Dot Above]O2max.

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Prolonged erythropoietin treatment does not impact gene expression in human skeletal muscle

Abstract: Erythropoietin is unlikely to exert direct effects in human skeletal muscle due to a lack of Epo-R protein. Furthermore, prolonged ESA treatment does not seem to exert either direct or indirect effects on skeletal muscle gene expression.

Cited by 9 publications

References 30 publications

Growth Hormone and Insulin Signaling in Acromegaly: Impact of Surgery Versus Somatostatin Analog Treatment

Growth Hormone and Insulin Signaling in Acromegaly: Impact of Surgery Versus Somatostatin Analog Treatment

Erythropoietin administration alone or in combination with endurance training affects neither skeletal muscle morphology nor angiogenesis in healthy young men

Comparative Effects of Aerobic Training and Erythropoietin on Oxygen Uptake in Untrained Humans

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