title: Metabolic and signaling alterations in dystrophin-deficient hearts precede overt cardiomyopathy.
abstract: The cytoskeletal protein dystrophin has been implicated in hereditary and acquired forms of cardiomyopathy. However, much remains to be learned about the role of dystrophin in the heart. We hypothesized that the dystrophin-deficient heart displays early alterations in energy metabolism that precede overt cardiomyopathy. We evaluated the metabolic and functional phenotype of dystrophin-deficient mdx mouse hearts at 10-12 weeks, when no major histological or echocardiographic abnormalities are reported. Ex vivo working mdx heart perfusions with stable isotopes revealed a marked shift in substrate fuel selection from fatty acids to carbohydrates associated with enhanced oxygen consumption. They also unmasked in the mdx heart: (i) compromised cardiac contractile function and efficiency, (ii) reduced cellular integrity, and (iii) exacerbated alterations in mitochondrial citric acid cycle-related parameters and in nutrient signaling pathways related to Akt. The observed shift in substrate selection cannot be explained by metabolic gene remodeling. However, mdx mice hearts showed an increased expression of the atrial natriuretic factor (anf) gene, an activator of the nitric oxide (NO)/cGMP signaling pathway and marker of cardiac remodeling, and, only as the cardiomyopathy progresses (at 25 weeks of age), an increased expression of the alpha1 subunit of soluble guanylate cyclase, which is known to negatively correlate with the activity NO/cGMP pathway. Collectively, our results highlight early metabolic and signaling alterations in the dystrophin-deficient heart, which may predispose these hearts to contractile dysfunction and sarcolemmal fragility. They also suggest the presence of a "sub-clinical" defect in the NO/cGMP pathway, which in vivo, at an early age, may be compensated by enhanced anf gene expression.
authors.affiliation: Montreal Heart Institute and University of Montreal, 5000 Belanger St., Montreal, Quebec, Canada H1T 1C8.
authors.forename: Maya
authors.initials: M
authors.lastname: Khairallah
authors.forename: Ramzi
authors.initials: R
authors.lastname: Khairallah
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism; D009202:Cardiomyopathies / Q000378:metabolism* / Q000503:physiopathology; D002951:Citrates / Q000096:biosynthesis; D002952:Citric Acid Cycle; D006152:Cyclic GMP / Q000378:metabolism; D016189:Dystrophin / Q000172:deficiency*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D016277:Ventricular Function, Left
chemical_list: D002951:Citrates; D016189:Dystrophin; D005227:Fatty Acids; D011773:Pyruvates; D012333:RNA, Messenger; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP