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Scientific Articles

Improvement of Duchenne Muscular Dystrophy Phenotype Following Obestatin Treatment

key information

source: Journal of Cachexia, Sarcopenia and Muscle

authors: González-Sánchez J, Sánchez-Temprano A, Cid-Díaz T, Pabst-Fernández R, Mosteiro CS, Gallego R, Nogueiras R, Casabiell X, Butler-Browne GS, Mouly V, Relova JL, Pazos Y, Camiña JP

summary/abstract:

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.

organization: Complejo Hospitalario Universitario de Santiago (CHUS), Spain; Universidad de Santiago de Compostela (USC), Spain; Sorbonne Universités, France; Laboratorio de Patología Digestiva, Spain

DOI: 10.1002/jcsm.12338

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