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Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment

BACKGROUND: This study was performed to test the therapeutic potential of obestatin, an autocrine anabolic factor regulating skeletal muscle repair, to ameliorate the Duchenne muscular dystrophy (DMD) phenotype. METHODS AND RESULTS: Using a multidisciplinary approach, we characterized the ageing‐rel...

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Autores principales: González‐Sánchez, Jessica, Sánchez‐Temprano, Agustín, Cid‐Díaz, Tania, Pabst‐Fernández, Regina, Mosteiro, Carlos S., Gallego, Rosalía, Nogueiras, Ruben, Casabiell, Xesús, Butler‐Browne, Gillian S., Mouly, Vincent, Relova, José Luis, Pazos, Yolanda, Camiña, Jesús P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240759/
https://www.ncbi.nlm.nih.gov/pubmed/30216693
http://dx.doi.org/10.1002/jcsm.12338
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author González‐Sánchez, Jessica
Sánchez‐Temprano, Agustín
Cid‐Díaz, Tania
Pabst‐Fernández, Regina
Mosteiro, Carlos S.
Gallego, Rosalía
Nogueiras, Ruben
Casabiell, Xesús
Butler‐Browne, Gillian S.
Mouly, Vincent
Relova, José Luis
Pazos, Yolanda
Camiña, Jesús P.
author_facet González‐Sánchez, Jessica
Sánchez‐Temprano, Agustín
Cid‐Díaz, Tania
Pabst‐Fernández, Regina
Mosteiro, Carlos S.
Gallego, Rosalía
Nogueiras, Ruben
Casabiell, Xesús
Butler‐Browne, Gillian S.
Mouly, Vincent
Relova, José Luis
Pazos, Yolanda
Camiña, Jesús P.
author_sort González‐Sánchez, Jessica
collection PubMed
description BACKGROUND: This study was performed to test the therapeutic potential of obestatin, an autocrine anabolic factor regulating skeletal muscle repair, to ameliorate the Duchenne muscular dystrophy (DMD) phenotype. METHODS AND RESULTS: Using a multidisciplinary approach, we characterized the ageing‐related preproghrelin/GPR39 expression patterns in tibialis anterior (TA) muscles of 4‐, 8‐, and 18‐week‐old mdx mice (n = 3/group) and established the effects of obestatin administration at this level in 8‐week‐old mdx mice (n = 5/group). The findings were extended to in vitro effects on human immortalized DMD myotubes. An analysis of TAs revealed an age‐related loss of preproghrelin expression, as precursor of obestatin, in mdx mice. Administration of obestatin resulted in a significant increase in tetanic specific force (33.0% ± 1.5%, P < 0.05), compared with control mdx mice. Obestatin‐treated TAs were characterized by reduction of fibres with centrally located nuclei (10.0% ± 1.2%, P < 0.05) together with an increase in the number of type I fibres (25.2% ± 1.7%, P < 0.05) associated to histone deacetylases/myocyte enhancer factor‐2 and peroxisome proliferator‐activated receptor‐gamma coactivator 1α axis, and down‐regulation of ubiquitin E3‐ligases by inactivation of FoxO1/4, indexes of muscle atrophy. Obestatin reduced the level of contractile damage and tissue fibrosis. These observations correlated with decline in serum creatine kinase (58.8 ± 15.2, P < 0.05). Obestatin led to stabilization of the sarcolemma by up‐regulation of utrophin, α‐syntrophin, β‐dystroglycan, and α7β1‐integrin proteins. These pathways were also operative in human DMD myotubes. CONCLUSIONS: These results highlight the potential of obestatin as a peptide therapeutic for preserving muscle integrity in DMD, thus allowing a better efficiency of gene or cell therapy in a combined therapeutic approach.
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spelling pubmed-62407592018-12-01 Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment González‐Sánchez, Jessica Sánchez‐Temprano, Agustín Cid‐Díaz, Tania Pabst‐Fernández, Regina Mosteiro, Carlos S. Gallego, Rosalía Nogueiras, Ruben Casabiell, Xesús Butler‐Browne, Gillian S. Mouly, Vincent Relova, José Luis Pazos, Yolanda Camiña, Jesús P. J Cachexia Sarcopenia Muscle Original Articles BACKGROUND: This study was performed to test the therapeutic potential of obestatin, an autocrine anabolic factor regulating skeletal muscle repair, to ameliorate the Duchenne muscular dystrophy (DMD) phenotype. METHODS AND RESULTS: Using a multidisciplinary approach, we characterized the ageing‐related preproghrelin/GPR39 expression patterns in tibialis anterior (TA) muscles of 4‐, 8‐, and 18‐week‐old mdx mice (n = 3/group) and established the effects of obestatin administration at this level in 8‐week‐old mdx mice (n = 5/group). The findings were extended to in vitro effects on human immortalized DMD myotubes. An analysis of TAs revealed an age‐related loss of preproghrelin expression, as precursor of obestatin, in mdx mice. Administration of obestatin resulted in a significant increase in tetanic specific force (33.0% ± 1.5%, P < 0.05), compared with control mdx mice. Obestatin‐treated TAs were characterized by reduction of fibres with centrally located nuclei (10.0% ± 1.2%, P < 0.05) together with an increase in the number of type I fibres (25.2% ± 1.7%, P < 0.05) associated to histone deacetylases/myocyte enhancer factor‐2 and peroxisome proliferator‐activated receptor‐gamma coactivator 1α axis, and down‐regulation of ubiquitin E3‐ligases by inactivation of FoxO1/4, indexes of muscle atrophy. Obestatin reduced the level of contractile damage and tissue fibrosis. These observations correlated with decline in serum creatine kinase (58.8 ± 15.2, P < 0.05). Obestatin led to stabilization of the sarcolemma by up‐regulation of utrophin, α‐syntrophin, β‐dystroglycan, and α7β1‐integrin proteins. These pathways were also operative in human DMD myotubes. CONCLUSIONS: These results highlight the potential of obestatin as a peptide therapeutic for preserving muscle integrity in DMD, thus allowing a better efficiency of gene or cell therapy in a combined therapeutic approach. John Wiley and Sons Inc. 2018-09-14 2018-12 /pmc/articles/PMC6240759/ /pubmed/30216693 http://dx.doi.org/10.1002/jcsm.12338 Text en © 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
González‐Sánchez, Jessica
Sánchez‐Temprano, Agustín
Cid‐Díaz, Tania
Pabst‐Fernández, Regina
Mosteiro, Carlos S.
Gallego, Rosalía
Nogueiras, Ruben
Casabiell, Xesús
Butler‐Browne, Gillian S.
Mouly, Vincent
Relova, José Luis
Pazos, Yolanda
Camiña, Jesús P.
Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment
title Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment
title_full Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment
title_fullStr Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment
title_full_unstemmed Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment
title_short Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment
title_sort improvement of duchenne muscular dystrophy phenotype following obestatin treatment
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240759/
https://www.ncbi.nlm.nih.gov/pubmed/30216693
http://dx.doi.org/10.1002/jcsm.12338
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