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Heme Oxygenase-1 Influences Satellite Cells and Progression of Duchenne Muscular Dystrophy in Mice.
Antioxid Redox Signal. 2018 07 10; 29(2):128-148.AR

Abstract

AIMS

Muscle damage in Duchenne muscular dystrophy (DMD) caused by the lack of dystrophin is strongly linked to inflammation. Heme oxygenase-1 (HO-1; Hmox1) is an anti-inflammatory and cytoprotective enzyme affecting myoblast differentiation by inhibiting myomiRs. The role of HO-1 has not been so far well addressed in DMD.

RESULTS

In dystrophin-deficient mdx mice, expression of Hmox1 in limb skeletal muscles and diaphragm is higher than in wild-type animals, being consistently elevated from 8 up to 52 weeks, both in myofibers and inflammatory leukocytes. Accordingly, HO-1 expression is induced in muscles of DMD patients. Pharmacological inhibition of HO-1 activity or genetic ablation of Hmox1 aggravates muscle damage and inflammation in mdx mice. Double knockout animals (Hmox1-/-mdx) demonstrate impaired exercise capacity in comparison with mdx mice. Interestingly, in contrast to the effect observed in muscle fibers, in dystrophin-deficient muscle satellite cells (SCs) expression of Hmox1 is decreased, while MyoD, myogenin, and miR-206 are upregulated compared with wild-type counterparts. Mdx SCs demonstrate disturbed and enhanced differentiation, which is further intensified by Hmox1 deficiency. RNA sequencing revealed downregulation of Atf3, MafK, Foxo1, and Klf2 transcription factors, known to activate Hmox1 expression, as well as attenuation of nitric oxide-mediated cGMP-dependent signaling in mdx SCs. Accordingly, treatment with NO-donor induces Hmox1 expression and inhibits differentiation. Finally, differentiation of mdx SCs was normalized by CO, a product of HO-1 activity. Innovation and Conclusions: HO-1 is induced in DMD, and HO-1 inhibition aggravates DMD pathology. Therefore, HO-1 can be considered a therapeutic target to alleviate this disease. Antioxid. Redox Signal. 00, 000-000.

Authors+Show Affiliations

1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland . 2 Department of Clinical Immunology and Transplantology, Institute of Paediatrics, Medical College, Jagiellonian University , Krakow, Poland .3 Department of Neurology, Medical University of Warsaw , Warsaw, Poland .3 Department of Neurology, Medical University of Warsaw , Warsaw, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Jagiellonian University , Krakow, Poland .

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29669436

Citation

Pietraszek-Gremplewicz, Katarzyna, et al. "Heme Oxygenase-1 Influences Satellite Cells and Progression of Duchenne Muscular Dystrophy in Mice." Antioxidants & Redox Signaling, vol. 29, no. 2, 2018, pp. 128-148.
Pietraszek-Gremplewicz K, Kozakowska M, Bronisz-Budzynska I, et al. Heme Oxygenase-1 Influences Satellite Cells and Progression of Duchenne Muscular Dystrophy in Mice. Antioxid Redox Signal. 2018;29(2):128-148.
Pietraszek-Gremplewicz, K., Kozakowska, M., Bronisz-Budzynska, I., Ciesla, M., Mucha, O., Podkalicka, P., Madej, M., Glowniak, U., Szade, K., Stepniewski, J., Jez, M., Andrysiak, K., Bukowska-Strakova, K., Kaminska, A., Kostera-Pruszczyk, A., Jozkowicz, A., Loboda, A., & Dulak, J. (2018). Heme Oxygenase-1 Influences Satellite Cells and Progression of Duchenne Muscular Dystrophy in Mice. Antioxidants & Redox Signaling, 29(2), 128-148. https://doi.org/10.1089/ars.2017.7435
Pietraszek-Gremplewicz K, et al. Heme Oxygenase-1 Influences Satellite Cells and Progression of Duchenne Muscular Dystrophy in Mice. Antioxid Redox Signal. 2018 07 10;29(2):128-148. PubMed PMID: 29669436.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Heme Oxygenase-1 Influences Satellite Cells and Progression of Duchenne Muscular Dystrophy in Mice. AU - Pietraszek-Gremplewicz,Katarzyna, AU - Kozakowska,Magdalena, AU - Bronisz-Budzynska,Iwona, AU - Ciesla,Maciej, AU - Mucha,Olga, AU - Podkalicka,Paulina, AU - Madej,Magdalena, AU - Glowniak,Urszula, AU - Szade,Krzysztof, AU - Stepniewski,Jacek, AU - Jez,Mateusz, AU - Andrysiak,Kalina, AU - Bukowska-Strakova,Karolina, AU - Kaminska,Anna, AU - Kostera-Pruszczyk,Anna, AU - Jozkowicz,Alicja, AU - Loboda,Agnieszka, AU - Dulak,Jozef, Y1 - 2018/05/23/ PY - 2018/4/20/pubmed PY - 2019/7/11/medline PY - 2018/4/20/entrez KW - heme oxygenase-1 KW - inflammation KW - microRNA KW - muscle satellite cells KW - muscular dystrophy KW - skeletal muscle SP - 128 EP - 148 JF - Antioxidants & redox signaling JO - Antioxid Redox Signal VL - 29 IS - 2 N2 - AIMS: Muscle damage in Duchenne muscular dystrophy (DMD) caused by the lack of dystrophin is strongly linked to inflammation. Heme oxygenase-1 (HO-1; Hmox1) is an anti-inflammatory and cytoprotective enzyme affecting myoblast differentiation by inhibiting myomiRs. The role of HO-1 has not been so far well addressed in DMD. RESULTS: In dystrophin-deficient mdx mice, expression of Hmox1 in limb skeletal muscles and diaphragm is higher than in wild-type animals, being consistently elevated from 8 up to 52 weeks, both in myofibers and inflammatory leukocytes. Accordingly, HO-1 expression is induced in muscles of DMD patients. Pharmacological inhibition of HO-1 activity or genetic ablation of Hmox1 aggravates muscle damage and inflammation in mdx mice. Double knockout animals (Hmox1-/-mdx) demonstrate impaired exercise capacity in comparison with mdx mice. Interestingly, in contrast to the effect observed in muscle fibers, in dystrophin-deficient muscle satellite cells (SCs) expression of Hmox1 is decreased, while MyoD, myogenin, and miR-206 are upregulated compared with wild-type counterparts. Mdx SCs demonstrate disturbed and enhanced differentiation, which is further intensified by Hmox1 deficiency. RNA sequencing revealed downregulation of Atf3, MafK, Foxo1, and Klf2 transcription factors, known to activate Hmox1 expression, as well as attenuation of nitric oxide-mediated cGMP-dependent signaling in mdx SCs. Accordingly, treatment with NO-donor induces Hmox1 expression and inhibits differentiation. Finally, differentiation of mdx SCs was normalized by CO, a product of HO-1 activity. Innovation and Conclusions: HO-1 is induced in DMD, and HO-1 inhibition aggravates DMD pathology. Therefore, HO-1 can be considered a therapeutic target to alleviate this disease. Antioxid. Redox Signal. 00, 000-000. SN - 1557-7716 UR - https://www.unboundmedicine.com/medline/citation/29669436/Heme_Oxygenase_1_Influences_Satellite_Cells_and_Progression_of_Duchenne_Muscular_Dystrophy_in_Mice_ L2 - https://www.liebertpub.com/doi/10.1089/ars.2017.7435?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -