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Abdel-Halim, Samy M.
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Publications (8 of 8) Show all publications
Basic, V. T., Jacobsen, A., Sirsjö, A. & Abdel-Halim, S. (2014). TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes. International Journal of Molecular Medicine, 34(1), 228-236
Open this publication in new window or tab >>TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes
2014 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 34, no 1, p. 228-236Article in journal (Refereed) Published
Abstract [en]

Decreased skeletal muscle capillarization is considered to significantly contribute to the development of pulmonary cachexia syndrome (PCS) and progressive muscle wasting in several chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). It is unclear to which extent the concurrent presence of systemic inflammation contributes to decreased skeletal muscle capillarization under these conditions. The present study was designed to examine in vitro the effects of the pro-inflammatory cytokine, tumor necrosis factor (TNF), on the regulation of hypoxia-angiogenesis signal transduction and capillarization in skeletal muscles. For this purpose, fully differentiated C2C12 skeletal muscle myocytes were stimulated with TNF and maintained under normoxic or hypoxic conditions. The expression levels of the putative elements of the hypoxia-angiogenesis signaling cascade were examined using qPCR, western blot analysis and immunofluorescence. Under normoxic conditinos, TNF stimulation increased the protein expression of anti-angiogenic von-Hippel Lindau (VHL), prolyl hydroxylase (PHD)2 and ubiquitin conjugating enzyme 2D1 (Ube2D1), as well as the total ubiquitin content in the skeletal muscle myocytes. By contrast, the expression levels of hypoxia-inducible factor 1‑α (HIF1-α) and those of its transcriptional targets, vascular endothelial growth factor (VEGF)A and glucose transporter 1 (Glut1), were markedly reduced. In addition, hypoxia increased the expression of the VHL transcript and further elevated the VHL protein expression levels in C2C12 myocytes following TNF stimulation. Consequently, an impaired angiogenic potential was observed in the TNF-stimulated myocytes during hypoxia. In conclusion, TNF increases VHL expression and disturbs hypoxia-angiogenesis signal transduction in skeletal muscle myocytes. The current findings provide a mechanism linking systemic inflammation and impaired angiogenesis in skeletal muscle. This is particularly relevant to further understanding the mechanisms mediating muscle wasting and cachexia in patients with chronic inflammatory diseases, such as COPD.

Place, publisher, year, edition, pages
Spandidos Publications, 2014
National Category
Medical Biotechnology
Research subject
Medical Disability Research
Identifiers
urn:nbn:se:oru:diva-35141 (URN)10.3892/ijmm.2014.1776 (DOI)000338178000027 ()24820910 (PubMedID)2-s2.0-84902649801 (Scopus ID)
Available from: 2014-05-25 Created: 2014-05-25 Last updated: 2018-06-07Bibliographically approved
Krivospitskaya, O., Elmabsout, A. A., Sundman, E., Söderström, L. A., Ovchinnikova, O., Gidlöf, A. C., . . . Olofsson, P. S. (2012). A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis. Molecular medicine (Cambridge, Mass. Print), 18(1), 712-718
Open this publication in new window or tab >>A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis
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2012 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, no 1, p. 712-718Article in journal (Refereed) Published
Abstract [en]

All-trans retinoic acid, controlled by CYP26 enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26B1 in atherosclerosis and effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries and CYP26B1 and the macrophage marker CD68 co-localized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic than normal arteries. Databases were queried for non-synonymous CYP26B1 SNPs and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophage-like cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.

Place, publisher, year, edition, pages
New York, USA: The Feinstein Institute for Medical Research, 2012
National Category
Medical and Health Sciences Biochemistry and Molecular Biology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-23259 (URN)10.2119/molmed.2012.00094 (DOI)000306034400018 ()22415012 (PubMedID)2-s2.0-84887594213 (Scopus ID)
Funder
Swedish Heart Lung FoundationSwedish Society for Medical Research (SSMF)Wenner-Gren Foundations
Note

Funding Agencies:

Swedish Health Care Sciences Postgraduate School (NFVO) at Karolinska Institutet 

Bergwall's Foundation 

Available from: 2012-06-05 Created: 2012-06-05 Last updated: 2018-08-27Bibliographically approved
Basic, V. T., Tadele, E., Elmabsout, A. A., Yao, H., Rahman, I., Sirsjö, A. & Abdel-Halim, S. M. (2012). Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle. American Journal of Physiology - Lung cellular and Molecular Physiology, 303(6), L519-L527
Open this publication in new window or tab >>Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle
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2012 (English)In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 303, no 6, p. L519-L527Article in journal (Refereed) Published
Abstract [en]

Cigarette smoke (CS) is a well established risk factor in the development of chronic obstructive pulmonary disease (COPD). In contrast, the extent to which CS exposure contributes to the development of the systemic manifestations of COPD, such as skeletal muscle dysfunction and wasting remains largely unknown. Decreased skeletal muscle capillarization has been previously reported in early stages of COPD and might play an important role in the development of COPD-associated skeletal muscle abnormalities. To investigate the effects of chronic CS exposure on skeletal muscle capillarization and exercise tolerance a mouse model of CS exposure was used. The129/SvJ mice were exposed to CS for 6 months, and the expression of putative elements of the hypoxia-angiogenic signaling cascade as well as muscle capillarization were studied. Additionally, functional tests assessing exercise tolerance/endurance were performed in mice. Compared to controls, skeletal muscles from CS-exposed mice exhibited significantly enhanced expression of von Hippel-Lindau tumor suppressor (VHL), ubiquitin-conjugating enzyme E2D1 (UBE2D1) and prolyl hydroxylase-2 (PHD2). In contrast, hypoxia-inducible factor-1 (HIF1-α) and vascular endothelial growth factor (VEGF) expression was reduced. Furthermore, reduced muscle fiber cross-sectional area, decreased skeletal muscle capillarization, and reduced exercise tolerance were also observed in CS-exposed animals. Taken together, the current results provide evidence linking chronic CS exposure and induction of VHL expression in skeletal muscles leading towards impaired hypoxia-angiogenesis signal transduction, reduced muscle fiber cross-sectional area and decreased exercise tolerance.

Place, publisher, year, edition, pages
Bethesda, USA: American Physiological Society, 2012
Keywords
Capillaries, chronic obstructive pulmonary disease, hypoxia inducible factor-1 alpha, pulmonary cachexia syndrome, vascular endothelial growth factor
National Category
Medical and Health Sciences Physiotherapy
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-24177 (URN)10.1152/ajplung.00007.2012 (DOI)000309109300005 ()22842216 (PubMedID)2-s2.0-84866418091 (Scopus ID)
Funder
NIH (National Institute of Health)
Note

Funding Agencies:

Olle Engkvist Byggmastare Fund, Sweden

NIEHS Environmental Health Science Center grant 

Available from: 2012-07-31 Created: 2012-07-31 Last updated: 2018-05-09Bibliographically approved
Eliason, G., Abdel-Halim, S. M., Piehl-Aulin, K. & Kadi, F. (2010). Alterations in the muscle-to-capillary interface in patients with different degrees of chronic obstructive pulmonary disease. Respiratory research (Online), 11, Article ID 97.
Open this publication in new window or tab >>Alterations in the muscle-to-capillary interface in patients with different degrees of chronic obstructive pulmonary disease
2010 (English)In: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 11, article id 97Article in journal (Refereed) Published
Abstract [en]

Background: It is hypothesized that decreased capillarization of limb skeletal muscle is implicated in the decreased exercise tolerance in COPD patients. We have recently demonstrated decreased number of capillaries per muscle fibre (CAF) but no changes in CAF in relation to fibre area (CAFA), which is based on the diffusion distance between the capillary and muscle fibre. The aim of the current study is to investigate the muscle-to-capillary interface which is an important factor involved in oxygen supply to the muscle that has previously been suggested to be a more sensitive marker for changes in the capillary bed compared to CAF and CAFA.

Methods: 23 COPD patients and 12 age-matched healthy subjects participated in the study. Muscle-to-capillary interface was assessed in muscle biopsies from the tibialis anterior muscle using the following parameters:

1) The capillary-to-fibre ratio (C:Fi) which is defined as the sum of the fractional contributions of all capillary contacts around the fibre

2) The ratio between C:Fi and the fibre perimeter (CFPE-index)

3) The ratio between length of capillary and fibre perimeter (LC/PF) which is also referred to as the index of tortuosity.

Exercise capacity was determined using the 6-min walking test.

Results: A positive correlation was found between CFPE-index and ascending disease severity with CFPE-index for type I fibres being significantly lower in patients with moderate and severe COPD. Furthermore, a positive correlation was observed between exercise capacity and CFPE-index for both type I and type IIa fibres.

Conclusion: It can be concluded that the muscle-to-capillary interface is disturbed in the tibialis anterior muscle in patients with COPD and that interface is strongly correlated to increased disease severity and to decreased exercise capacity in this patient group.

 

Place, publisher, year, edition, pages
London, United Kingdom: BioMed Central, 2010
Keywords
COPD, muscle-capillary interface, CFPE-index, LC/PF, tortuosity
National Category
Physiology Medical and Health Sciences
Research subject
Physiology; Medicine
Identifiers
urn:nbn:se:oru:diva-12493 (URN)10.1186/1465-9921-11-97 (DOI)000282550500002 ()20633289 (PubMedID)2-s2.0-77956692758 (Scopus ID)
Available from: 2010-11-19 Created: 2010-11-18 Last updated: 2018-09-11Bibliographically approved
Piehl-Aulin, K., Jones, I., Lindvall, B., Magnuson, A. & Abdel-Halim, S. M. (2009). Increased serum inflammatory markers in the absence of clinical and skeletal muscle inflammation in patients with chronic obstructive pulmonary disease. Respiration, 78(2), 191-196
Open this publication in new window or tab >>Increased serum inflammatory markers in the absence of clinical and skeletal muscle inflammation in patients with chronic obstructive pulmonary disease
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2009 (English)In: Respiration, ISSN 0025-7931, E-ISSN 1423-0356, Vol. 78, no 2, p. 191-196Article in journal (Refereed) Published
Abstract [en]

Background: Muscle wasting and cachexia are common occurrences in patients with chronic obstructive pulmonary disease (COPD). Objectives: The current study aimed to investigate markers of inflammation in the circulation and skeletal muscle that might be associated with development of muscle wasting. Methods: Three groups of patients with mild, moderate and severe COPD and matched healthy controls were recruited. Serum levels of C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), IL-6, IL-8, TNF-α, cortisol, insulin-like growth factor 1 (IGF-1), leptin and ghrelin were analysed. Skeletal muscle inflammation was investigated microscopically using a panel of antibodies and standard staining for inflammatory cell infiltration. Results: All COPD patients were clinically stable, with no sign of inflammation and normal CRP values. Compared to controls, significantly increased hs-CRP levels were observed in all COPD patient groups. Significant rises in IL-6 levels were first observed in moderate COPD, while IL-8 levels were significantly elevated at the late severe stage. Circulating levels of TNF-α, cortisol, IGF-1, leptin and ghrelin were similar to control levels. No microscopic signs of skeletal muscle inflammation were observed. Conclusion: Our results identify hs-CRP as an early marker of inflammation that is significantly increased in the circulation even in mild COPD. Serum interleukin levels appear to be increased with disease progress. These changes were manifested in the absence of any clinical signs of disease exacerbation, evidence of skeletal muscle inflammation or hormonal changes. © 2009 S. Karger AG, Basel.

Keywords
Chronic obstructive pulmonary disease, High sensitivity C-reactive protein, Inflammation, skeletal muscle
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-14216 (URN)10.1159/000207793 (DOI)
Available from: 2011-01-25 Created: 2011-01-25 Last updated: 2018-04-16Bibliographically approved
Jatta, K., Eliason, G., Portela-Gomes, G. M., Grimelius, L., Caro, O., Nilholm, L., . . . Abdel-Halim, S. M. (2009). Overexpression of von Hippel-Lindau protein in skeletal muscles of patients with chronic obstructive pulmonary disease. Journal of Clinical Pathology, 62(1), 70-76
Open this publication in new window or tab >>Overexpression of von Hippel-Lindau protein in skeletal muscles of patients with chronic obstructive pulmonary disease
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2009 (English)In: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 62, no 1, p. 70-76Article in journal (Refereed) Published
Abstract [en]

Background/aim: A Significant number of patients with chronic obstructive pulmonary disease (COPD) exhibit skeletal muscle wasting and decreased capillary area formation which have been correlated to increased mortality. The current study aimed to determine the molecular mechanisms mediating decreased capillary formation in COPD.

Methods: Twenty-four COPD patients and twelve matching controls were recruited. COPD patients were divided into mild, moderate and severe groups according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria. Skeletal muscle biopsies were obtained from the tibialis anterior muscle. Fibre typing and capillary formation together with messenger RNA (mRNA) expression of hypoxia-inducible factors (HIF-1á and HIF-3á ), vascular endothelial growth factors (VEGF-A, -B and -C isoforms) and von Hippel Lindau (VHL) were determined. VHL expression and localization was further studied by immunohistochemistry.

Results: Skeletal muscle capillary formation was significantly decreased with ascending disease severity. Compared to controls, a tendency to mRNA overexpression of HIF-1á, HIF-3á and VEGF isoforms was observed at mild and moderate COPD that decreased at the severe stage. By contrast, skeletal muscle biopsies from COPD patients exhibited significant overexpression of VHL both on the mRNA and protein levels by immunohistochemistry. VHL protein was further determined to be localized to satellite cells.

Conclusions: Overexpression of VHL was identified in the skeletal muscle of patients with COPD. Increased VHL activity may exert a negative impact on transducing the hypoxic signal and may contribute to decreased capillarization in skeletal muscles of patients with COPD.

Place, publisher, year, edition, pages
London: BMJ Publishing Group Ltd, 2009
National Category
Medical and Health Sciences Cell and Molecular Biology
Research subject
Pathology; Medicine
Identifiers
urn:nbn:se:oru:diva-3418 (URN)10.1136/jcp.2008.057190 (DOI)000262420400018 ()18818266 (PubMedID)2-s2.0-58349102711 (Scopus ID)
Available from: 2008-12-04 Created: 2008-12-04 Last updated: 2018-01-13Bibliographically approved
Eliason, G., Abdel-Halim, S., Arvidsson, B., Kadi, F. & Piehl-Aulin, K. (2009). Physical performance and muscular characteristics in different stages of COPD. Scandinavian Journal of Medicine and Science in Sports, 19(6), 865-870
Open this publication in new window or tab >>Physical performance and muscular characteristics in different stages of COPD
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2009 (English)In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 19, no 6, p. 865-870Article in journal (Refereed) Published
Abstract [en]

This study has examined exercise capacity and muscle morphology in patients with different severities of chronic obstructive pulmonary disease (COPD). Twenty-three patients and 12 healthy matched controls were recruited. Based on the severity of airflow obstruction, patients were divided into two subgroups. Exercise capacity was determined using a 6-min walk test. Muscle fiber composition, fiber area and number of satellite cells/muscle fiber were determined in muscle biopsies using immunohistochemistry. A progressive decline in exercise capacity was noted with ascending disease severity. Furthermore, a correlation between reduction in exercise capacity and changes in muscle fiber composition was observed in COPD. The group with severe and very severe COPD had a lower proportion of type I and a higher proportion of type IIa fibers compared with the other groups. In severe and very severe COPD, a reduction in fiber area of type IIa fibers was also seen. The number of satellite cells/muscle fiber did not differ between the groups. In conclusion, a decline in exercise capacity occurs already in mild and moderate COPD, indicating that the 6-min walk test is a reliable indicator of disease severity. Furthermore, changes in skeletal muscle morphology are associated with disease severity while muscle regenerative capacity is not altered.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2009
Keywords
Activities of Daily Living/*psychology, Adaptation; Psychological, Aged, Aged; 80 and over, Attitude to Health, Body Image, Dependency (Psychology), Female, Health Services Needs and Demand, Humans, Interpersonal Relations, Male, Middle Aged, Models; Psychological, Neoplasms/psychology, Nursing Methodology Research, Palliative Care/methods/*psychology, Power (Psychology), Quality of Life/psychology, Questionnaires, Respite Care/psychology, Self Concept, Social Support, Sweden
National Category
Medical and Health Sciences Physiology Respiratory Medicine and Allergy Sport and Fitness Sciences
Research subject
Physiology; Sports Science
Identifiers
urn:nbn:se:oru:diva-3417 (URN)10.1111/j.1600-0838.2008.00858.x (DOI)000272132200014 ()18980606 (PubMedID)2-s2.0-70450260481 (Scopus ID)
Available from: 2008-12-04 Created: 2008-12-04 Last updated: 2018-01-13Bibliographically approved
Basic, V. T., Jacobsen, A., Tadele, E., Banjop- Kharlyngdoh, J., Sirsjö, A. & Abdel-Halim, S. M.Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stress.
Open this publication in new window or tab >>Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stress
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Enhanced protein degradation via ubiquitin proteolytic system (UPS) was demonstrated to play an important role in the pathogenesis of cachexia syndrome and muscle wasting in patients with COPD and animal models of the disease. The role of cigarette smoke (CS) exposure in eliciting these abnormalities remains largely unknown. Usp19 is a member of UPS suggested to be involved in progressive muscle wasting in different catabolic conditions. However, factors regulating Usp19 expression, activity and correlation/s with CS-induced muscle atrophy remainunclear.

Methods: To address these questions, 129 SvJ mice were exposed to cigarette smoke for 6 months and the gastrocnemius muscles were collected. Expression levels of Usp19 as well as pivotal mediators of ER stress response have been studied using PCR, qPCR, western blot and immunofluorescence. Factors regulating muscle Usp19 expression were studied using in-silico analysis of Usp19 promoter as well as by stimulating C2C12 myocytes with different inducers of ER stress including hypoxia, TNF and tunicamycin. Finally, Usp19 expression was depleted in C2C12 myocytes using specific Usp19 siRNA quadriplex and the expression of pivotal myogenic regulators were analyzed.

Results: Usp19 mRNA expression was enhanced in skeletal muscles of CS-exposed mice. Concurrently, ER stress-associated Caspase 12 and Caspase 3 were activated in the CS-exposed group. Analysis of Usp19 promoter sequence revealed binding sites for ER stress response transcription factors such as HSF, STRE1 and AML1-α. Exposure of C2C12 myocytes to tunicamycin but not hypoxia elevated expression levels of Usp19. TNFstimulation elevated Usp19 protein expression but inhibited its RNA transcription in a dose- and time-dependent manner. Finally, Usp19 overexpression in tunicamycin-treated myocytes was accompanied by reduced expression of myosin heavy chain and tropomyosin and their levels were increased after knocking down Usp19 in C2C12 myocytes.

Conclusions: In summary, our data demonstrated elevated expression of Usp19 in skeletal muscles of CS-exposed 129 SvJ mice. Moreover, Usp19 overexpression was associated with muscle adaptations to ER stress and suppression of myogenesis. Taken together; our results might provide further insight into molecular mechanisms underlying development and progression of skeletal muscle abnormalities in response to chronic cigarette smoke exposure.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-38194 (URN)
Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-10-17Bibliographically approved
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