losartan-potassium and Muscular-Atrophy

Intracellular proteins continuously turn over by degradation and synthesis in all organ tissues. Owing to its irreversible nature, protein degradation is a highly selective process to avoid irreparable breakdown of cellular constituents, thereby disrupting cellular stability, integrity and signalling. The majority of intracellular proteins are degraded by the ubiquitin-proteasome system (UPS), a multi-enzyme process that involves the covalent conjugation of ubiquitin to a substrate protein and its recognition and degradation by the core multicomponent proteolytic complex of the UPS, the proteasome. In addition to labelling misfolded, damaged, aggregation-prone and intact but unneeded proteins for proteasomal degradation, ubiquitylation regulates a multitude of cellular processes, such as transcription, translation, endocytosis, and receptor activity and subcellular localization. In addition, the proteasome generates peptides for antigen presentation in the immune system and for further degradation by peptidases to provide amino acids for protein biosynthesis and gluconeogenesis. Alterations of the UPS or of protein substrates that render them more or less susceptible to degradation are responsible for disorders associated with renal cell dysfunction. In this Review, we provide insight into the elegant and complex nature of UPS-mediated proteostasis and focus on its established and potential roles in renal cell physiology and pathophysiology.

Topics: Autophagy; Biological Transport; Erythropoietin; Glucose; Homeostasis; Humans; Kidney; Kidney Diseases; Lysosomes; Muscular Atrophy; Podocytes; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Sodium; Ubiquitinated Proteins; Ubiquitination; von Hippel-Lindau Disease; Water-Electrolyte Balance

To compare usual care with a home-based individualized exercise program (HBIEP) in patients receiving intensive treatment for multiple myeloma (MM)and epoetin alfa therapy.. Randomized trial with repeated measures of two groups (one experimental and one control) and an approximate 15-week experimental period.. Outpatient setting of the Myeloma Institute for Research and Therapy at the Rockfellow Cancer Center at the University of Arkansas for Medical Sciences.. 187 patients with newly diagnosed MM enrolled in a separate study evaluating effectiveness of the Total Therapy regimen, with or without thalidomide.. Measurements included the Profile of Mood States fatigue scale, Functional Assessment of Cancer Therapy-Fatigue, ActiGraph® recordings, 6-Minute Walk Test, and hemoglobin levels at baseline and before and after stem cell collection. Descriptive statistics were used to compare demographics and treatment effects, and repeated measures analysis of variance was used to determine effects of HBIEP.. Fatigue, nighttime sleep, performance (aerobic capacity) as dependent or outcome measures, and HBIEP combining strength building and aerobic exercise as the independent variable.. Both groups were equivalent for age, gender, race, receipt of thalidomide, hemoglobin levels, and type of treatment regimen for MM. No statistically significant differences existed among the experimental and control groups for fatigue, sleep, or performance (aerobic capacity). Statistically significant differences (p < 0.05) were found in each of the study outcomes for all patients as treatment progressed and patients experienced more fatigue and poorer nighttime sleep and performance (aerobic capacity).. The effect of exercise seemed to be minimal on decreasing fatigue, improving sleep, and improving performance (aerobic capacity).. Exercise is safe and has physiologic benefits for patients undergoing MM treatment; exercise combined with epoetin alfa helped alleviate anemia.

Topics: Adult; Affect; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Epoetin Alfa; Erythropoietin; Exercise; Fatigue; Female; Home Care Services; Humans; Male; Middle Aged; Models, Biological; Motor Activity; Multiple Myeloma; Muscular Atrophy; Peripheral Blood Stem Cell Transplantation; Polysomnography; Recombinant Proteins; Resistance Training; Sleep Disorders, Intrinsic; Thalidomide; Walking

Erythropoietin (EPO) promotes myelination and functional recovery in rodent peripheral nerve injury (PNI). While EPO receptors (EpoR) are present in Schwann cells, the role of EpoR in PNI recovery is unknown because of the lack of EpoR antagonists or Schwann cell-specific EpoR knockout animals.. Using the Cre-loxP system, we developed a myelin protein zero (Mpz) promoter-driven knockout mouse model of Schwann cell EpoR (MpzCre-EpoR. EPO treatment significantly accelerated functional recovery in control mice in contrast to significantly reduced functional recovery in Mpz-EpoR-KO mice. Significant muscle atrophy was found in the injured hindlimb of EPO-treated Mpz-EpoR-KO mice but not in EPO-treated control mice.. These preliminary findings provide direct evidence for an obligatory role of Schwann-cell specific EpoR for EPO-induced functional recovery and muscle atrophy following PNI.

Topics: Animals; Crush Injuries; Erythropoietin; Mice; Mice, Knockout; Muscular Atrophy; Peripheral Nerve Injuries; Receptors, Erythropoietin; Recovery of Function; Reverse Transcriptase Polymerase Chain Reaction; Schwann Cells; Sciatic Nerve

Peripheral nerve injury (PNI) often leads to significant functional loss in patients and poses a challenge to physicians since treatment options for improving functional outcomes are limited. Recent studies suggest that erythropoietin and glucocoticoids have beneficial effects as mediators of neuro-regenerative processes. We hypothesized that combination treatment with erythropoietin and glucocoticoids would have a synergistic effect on functional outcome after PNI.. Sciatic nerve crush injury was simulated in ten-week-old male C57BL/6 mice. The mice were divided into four groups according to the type of drugs administered (control, erythropoietin, dexamethasone, and erythropoietin with dexamethasone). Motor functional recovery was monitored by walking track analysis at serial time points up to 28 days after injury. Morphological analysis of the nerve was performed by immunofluorescent staining for neurofilament (NF) heavy chain and myelin protein zero (P0) in cross-sectional and whole-mount nerve preparations. Additionally, morphological analysis of the muscle was performed by Hematoxylin and eosin staining.. Combination treatment with erythropoietin and dexamethasone significantly improved the sciatic functional index at 3, 7, 14, and 28 days after injury. Fluorescence microscopy of cross sectional nerve revealed that the combination treatment increased the ratio of P0/NF-expressing axons. Furthermore, confocal microscopy of the whole-mount nerve revealed that the combination treatment increased the fluorescence intensity of P0 expression. The cross-sectional area and minimum Feret's diameter of the muscle fibers were significantly larger in the mice which received combination treatment than those in the controls.. Our results demonstrated that combination treatment with erythropoietin and dexamethasone accelerates functional recovery and reduces neurogenic muscle atrophy caused by PNI in mice, which may be attributed to the preservation of myelin and Schwann cell re-myelination. These findings may provide practical therapeutic options for patients with acute PNI.

Topics: Acute Disease; Animals; Axons; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Male; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Muscles; Muscular Atrophy; Myelin P0 Protein; Peripheral Nerve Injuries; Recovery of Function; Remyelination; Schwann Cells; Sciatic Nerve

Erythropoietin (EPO) is known to improve exercise performance by increasing oxygen blood transport and thus inducing a higher maximum oxygen uptake (VO2max). Furthermore, treatment with (or overexpression of) EPO induces protective effects in several tissues, including the myocardium. However, it is not known whether EPO exerts this protective effect when present at physiological levels. Given that EPO receptors have been identified in skeletal muscle, we hypothesized that EPO may have a direct, protective effect on this tissue. Thus, the objectives of the present study were to confirm a decrease in exercise performance and highlight muscle transcriptome alterations in a murine EPO functional knock-out model (the EPO-d mouse).. We determined VO2max peak velocity and critical speed in exhaustive runs in 17 mice (9 EPO-d animals and 8 inbred controls), using treadmill enclosed in a metabolic chamber. Mice were sacrificed 24h after a last exhaustive treadmill exercise at critical speed. The tibialis anterior and soleus muscles were removed and total RNA was extracted for microarray gene expression analysis.. The EPO-d mice's hematocrit was about 50% lower than that of controls (p<0.05) and their performance level was about 25% lower (p<0.001). A total of 1583 genes exhibited significant changes in their expression levels. However, 68 genes were strongly up-regulated (normalized ratio>1.4) and 115 were strongly down-regulated (normalized ratio<0.80). The transcriptome data mining analysis showed that the exercise in the EPO-d mice induced muscle hypoxia, oxidative stress and proteolysis associated with energy pathway disruptions in glycolysis and mitochondrial oxidative phosphorylation.. Our results showed that the lack of functional EPO induced a decrease in the aerobic exercise capacity. This decrease was correlated with the hematocrit and reflecting poor oxygen supply to the muscles. The observed alterations in the muscle transcriptome suggest that physiological concentrations of EPO exert both direct and indirect muscle-protecting effects during exercise. However, the signaling pathway involved in these protective effects remains to be described in detail.

Topics: Adenosine Triphosphate; Animals; Biological Transport; Cytoskeleton; Down-Regulation; Erythropoietin; Female; Hematocrit; Hypoxia; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Atrophy; Oligonucleotide Array Sequence Analysis; Oxygen Consumption; Physical Conditioning, Animal; Proteolysis; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Up-Regulation

Erythropoietin (Epo) and vascular growth factor (VEGF) are known to be involved in the regulation of cellular activity when oxygen transport is reduced as in anaemia or hypoxic conditions. Because it has been suggested that Epo could play a role in skeletal muscle development, regeneration, and angiogenesis, we aimed to assess Epo deficiency in both normoxia and hypoxia by using an Epo-deficient transgenic mouse model (Epo-TAg(h)). Histoimmunology, ELISA and real time RT-PCR did not show any muscle fiber atrophy or accumulation of active HIF-1alpha but an improvement of microvessel network and an upregulation of VEGFR2 mRNA in Epo-deficient gastrocnemius compared with Wild-Type one. In hypoxia, both models exhibit an upregulation of VEGF120 and VEGFR2 mRNA but no accumulation of Epo protein. EpoR mRNA is not up-regulated in both Epo-deficient and hypoxic gastrocnemius. These results suggest that muscle deconditioning observed in patients suffering from renal failure is not due to Epo deficiency.

Topics: Analysis of Variance; Animals; Erythropoietin; Histocytochemistry; Hypoxia; Hypoxia-Inducible Factor 1; Male; Mice; Mice, Transgenic; Microvessels; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Neovascularization, Physiologic; Receptors, Erythropoietin; Sarcomeres; Statistics, Nonparametric; Up-Regulation; Vascular Endothelial Growth Factors

To investigate the effect of exogenous erythropoietin (EPO) on the denervated muscle atrophy.. Twenty-four SD male rats, weighting 200-220 g were made the models of denervated gastrocnemius muscle after sciatic nerves were transected under the piriform muscle at the right lower leg, and were randomly divided into two groups (n=12). rhEPO (2500 U/kg) was injected daily into the denervated gastrocnemius muscle in EPO group, and normal saline was injected into the denervated gastrocnemius muscle in control group. To observe the general state of health of the experimental animal, the muscle wet weight, the muscle cell diameter, the cross section area, the protein amount, the percentage of the apoptotic muscle cells, and the Na+-K -ATPase and Ca2+ -ATPase activities were measured 2 and 4 weeks after operation.. All experimental animals were survived during experiment without cut infection, and all animals could walk with pulling the right knee. At 4 weeks after operation, 7 cases showed ulcer in the right heel, including 5 in the control group and 2 in the EPO group. At 2 and 4 weeks after operation, the muscle wet weight in EPO group was (885.59 +/- 112.35) and (697.62 +/- 94.74) g, respectively; in control group, it was (760.63 +/- 109.05) and (458.71 +/- 58.76) g, respectively; indicating significant differences between two groups (P < 0.01). The protein amount in EPO group was (77.37 +/- 5.24) and (66.37 +/- 4.87) mg/mL, respectively; in control group, it was (65.39 +/- 4.97) and (54.62 +/- 6.32) mg/mL: indicating significant differences between two groups (P < 0.01). At 2 and 4 weeks after operation, the myofibrillar shapes were nearly normal in EPO group while there were muscle fiber atrophy, some collapse and obviously hyperelastosis between muscle bundle. There were significant differences in the muscle cell diameter and the cross section between two groups (P < 0.01). However, the percentage of the apoptotic muscle cells was 11.80% +/- 1.74% and 28.47% +/- 1.81% in control group, respectively, which was significantly smaller than that in EPO group (21.48% +/- 2.21% and 55.89% +/- 2.88%, P < 0.01). At 2 and 4 weeks after operation, Na+-K+ -ATPase and Ca2+ -ATPase activities in EPO group were higher than those in control group (P < 0.01).. EPO can delay the denervated muscle atrophy.

Topics: Animals; Calcium-Transporting ATPases; Disease Models, Animal; Erythropoietin; Male; Muscular Atrophy; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase